Breaking barriers to novel analgesic drug development

A Corrigendum to this article was published on 06 October 2017

This article has been updated

Key Points

  • Pain is the primary reason why people seek medical care; more than 40% of the US population is affected by chronic pain.

  • Opioids, which are the most commonly used and often the most effective class of analgesics, produce tolerance, dependence and constipation, and are associated with major abuse liabilities. The respiratory depression associated with high doses has led to a catastrophic increase in the number of drug overdose deaths in the United States.

  • Several new or previously overlooked targets are gaining significant attention. In the field of G-protein-coupled receptors (GPCRs), these include new ligands targeting opioid receptor heteromers, different opioid receptor subtypes and biased agonists. Non-opioid GPCRs currently being pursued include cannabinoid receptor 2 (CB2), angiotensin type 2 receptor (AT2R) and chemokine receptors.

  • Various academic and industry groups are pursuing ion channel strategies by targeting sodium, potassium and calcium channels — specifically, certain Nav1.7, Nav1.8 and voltage-dependent calcium channel (Cavs) ligands are showing particular promise in early preclinical and clinical trials.

  • Several enzyme targets that modulate pain pathways are also being pursued.

  • Despite considerable efforts, there have been several high-profile failures of novel analgesics in the clinic.

  • Barriers that need to be overcome to develop efficacious analgesics include issues related to the lack of predictability of preclinical models in certain contexts, the translation of pathways from animal models to humans, exaggerated placebo effects and issues with clinical trial design.


Acute and chronic pain complaints, although common, are generally poorly served by existing therapies. This unmet clinical need reflects a failure to develop novel classes of analgesics with superior efficacy, diminished adverse effects and a lower abuse liability than those currently available. Reasons for this include the heterogeneity of clinical pain conditions, the complexity and diversity of underlying pathophysiological mechanisms, and the unreliability of some preclinical pain models. However, recent advances in our understanding of the neurobiology of pain are beginning to offer opportunities for developing novel therapeutic strategies and revisiting existing targets, including modulating ion channels, enzymes and G-protein-coupled receptors.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Mechanisms relevant for nociception and analgesia.
Figure 2: Peripheral analgesic drug discovery targets.

Change history

  • 23 June 2017

    In the original published article, the ligands RB-64 and PZM21 have been shown as attributed to Trevena in table 1 in the 'biased GPCR ligands' row. This error has been corrected in the HTML and PDF versions of the article.

  • 06 October 2017

    The compounds APD371,LY2828360, S-777469 and KHK6188 were incorrectly referred to as inhibitors of the cannabinoid receptors CB1 and CB2 in Table 1, when they are cannabinoid receptor agonists. In addition, KHK6188 is not currently in a Phase 2 clinical trial for neuropathic pain as stated in Table 1 and development of this agent has been discontinued. The error has been corrected in the html and pdf versions online.


  1. 1

    Dubois, M. Y., Gallagher, R. M. & Lippe, P. M. Pain medicine position paper. Pain Med. 10, 972–1000 (2009).

    PubMed  Google Scholar 

  2. 2

    Johannes, C. B., Le, T. K., Zhou, X., Johnston, J. A. & Dworkin, R. H. The prevalence of chronic pain in United States adults: results of an Internet-based survey. J. Pain 11, 1230–1239 (2010).

    PubMed  Google Scholar 

  3. 3

    Volkow, N. D. & McLellan, A. T. Opioid abuse in chronic pain — misconceptions and mitigation strategies. N. Engl. J. Med. 374, 1253–1263 (2016). This review highlights common misconceptions about abuse-related liabilities of prescription opioids and proposes strategies that could help to mitigate these risks.

    CAS  PubMed  Google Scholar 

  4. 4

    Decosterd, I. & Woolf, C. J. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87, 149–158 (2000). In this study, the authors describe a technique for modelling peripheral neuropathic pain in laboratory rodents.

    CAS  PubMed  Google Scholar 

  5. 5

    Honore, P. et al. Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience 98, 585–598 (2000).

    CAS  PubMed  Google Scholar 

  6. 6

    Costigan, M. et al. Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1. Brain 133, 2519–2527 (2010). This research article describes a putative human pain gene that could inform the selection of novel drug targets for patients with neuropathic pain. It may help to explain why some, but not all, people with nerve injury progress to chronic pain.

    PubMed  PubMed Central  Google Scholar 

  7. 7

    von Hehn, C. A., Baron, R. & Woolf, C. J. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron 73, 638–652 (2012). This work describes how the variable expression of sensory nerve injury symptoms can provide insights into the underlying pathophysiological mechanisms and guidance for the development of personalized pain therapies.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Ji, R. R., Xu, Z. Z. & Gao, Y. J. Emerging targets in neuroinflammation-driven chronic pain. Nat. Rev. Drug Discov. 13, 533–548 (2014). Here, the authors discuss emerging neuroinflammatory pain targets and describe potential therapeutic opportunities to target excessive neuroinflammation.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Latremoliere, A. & Woolf, C. J. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J. Pain 10, 895–926 (2009). This work describes the mechanisms and triggers that underlie the initiation and maintenance of central sensitization, and how they are altered by changes in the properties and expression patterns of glutamate receptors.

    PubMed  PubMed Central  Google Scholar 

  10. 10

    Basbaum, A. I., Bautista, D. M., Scherrer, G. & Julius, D. Cellular and molecular mechanisms of pain. Cell 139, 267–284 (2009). In this piece, the authors review the biological underpinnings of somatosensation at the circuit, cellular and subcellular levels, with particular emphasis on pain-related receptors and mechanisms.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Ossipov, M. H., Dussor, G. O. & Porreca, F. Central modulation of pain. J. Clin. Invest. 120, 3779–3787 (2010). This review explores evidence that central modulatory circuits can dramatically change the subjective experience of painful stimuli.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Vardeh, D., Mannion, R. J. & Woolf, C. J. Toward a mechanism-based approach to pain diagnosis. J. Pain 17, T50–T69 (2016). Here, the authors propose that identifying specific mechanisms that underlie chronic pain could provide the basis for a personalized-medicine approach to analgesia.

    PubMed  PubMed Central  Google Scholar 

  13. 13

    Woolf, C. J. Overcoming obstacles to developing new analgesics. Nat. Med. 16, 1241–1247 (2010). This article discusses the many complexities that have made the development of new analgesics so challenging.

    CAS  PubMed  Google Scholar 

  14. 14

    Andrews, N. A. et al. Ensuring transparency and minimization of methodologic bias in preclinical pain research: PPRECISE considerations. Pain 157, 901–909 (2016). Here, members of the Preclinical Pain Research Consortium for Investigating Safety and Efficacy (PPRECISE) working group propose new voluntary standards of scientific rigour and transparent reporting to promote more-efficient advancement of the search for new pain treatments.

    PubMed  Google Scholar 

  15. 15

    Singla, N. et al. Assay sensitivity of pain intensity versus pain relief in acute pain clinical trials: ACTTION systematic review and meta-analysis. J. Pain 16, 683–691 (2015). This meta-analysis found that for preclinical acute pain trials, readouts of total pain relief may be more sensitive to treatment than summed pain intensity differences.

    PubMed  Google Scholar 

  16. 16

    Finnerup, N. B. et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 14, 162–173 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Costigan, M., Scholz, J. & Woolf, C. J. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu. Rev. Neurosci. 32, 1–32 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Patapoutian, A., Tate, S. & Woolf, C. J. Transient receptor potential channels: targeting pain at the source. Nat. Rev. Drug Discov. 8, 55–68 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Woolf, C. J. Pain: morphine, metabolites, mambas, and mutations. Lancet Neurol. 12, 18–20 (2013).

    PubMed  Google Scholar 

  20. 20

    Woolf, C. J. & Salter, M. W. Neuronal plasticity: increasing the gain in pain. Science 288, 1765–1769 (2000). In this review, the authors conceptualize how plasticity in ascending sensory pathways may elicit pain hypersensitivity by increasing signal gain.

    CAS  PubMed  Google Scholar 

  21. 21

    Chiu, I. M., von Hehn, C. A. & Woolf, C. J. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat. Neurosci. 15, 1063–1067 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Woolf, C. J. What is this thing called pain? J. Clin. Invest. 120, 3742–3744 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Julius, D. & Basbaum, A. I. Molecular mechanisms of nociception. Nature 413, 203–210 (2001). Here, the authors describe molecular mechanisms of primary afferent neurons, their modality sensitivities and various transducers, peptides, lipids and growth factors that signal pain and mediate pain-related signals.

    CAS  PubMed  Google Scholar 

  24. 24

    Michaud, K., Bombardier, C. & Emery, P. Quality of life in patients with rheumatoid arthritis: does abatacept make a difference? Clin. Exp. Rheumatol. 25, S35–S45 (2007).

    CAS  PubMed  Google Scholar 

  25. 25

    Drenth, J. P. & Waxman, S. G. Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. J. Clin. Invest. 117, 3603–3609 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Woolf, C. J. Central sensitization: implications for the diagnosis and treatment of pain. Pain 152, S2–S15 (2011).

    PubMed  Google Scholar 

  27. 27

    Hains, B. C. et al. Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury. J. Neurosci. 23, 8881–8892 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Nassar, M. A. et al. Nerve injury induces robust allodynia and ectopic discharges in Nav1.3 null mutant mice. Mol. Pain 2, 33 (2006).

    PubMed  PubMed Central  Google Scholar 

  29. 29

    Dong, X. W. et al. Small interfering RNA-mediated selective knockdown of NaV1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience 146, 812–821 (2007).

    CAS  PubMed  Google Scholar 

  30. 30

    Jarvis, M. F. et al. A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl Acad. Sci. USA 104, 8520–8525 (2007).

    CAS  PubMed  Google Scholar 

  31. 31

    Ekberg, J. et al. muO-conotoxin MrVIB selectively blocks Nav1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits. Proc. Natl Acad. Sci. USA 103, 17030–17035 (2006).

    CAS  PubMed  Google Scholar 

  32. 32

    Gold, M. S. et al. Redistribution of NaV1.8 in uninjured axons enables neuropathic pain. J. Neurosci. 23, 158–166 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Joshi, S. K. et al. Involvement of the TTX-resistant sodium channel Nav 1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain 123, 75–82 (2006).

    CAS  PubMed  Google Scholar 

  34. 34

    Roza, C., Laird, J. M., Souslova, V., Wood, J. N. & Cervero, F. The tetrodotoxin-resistant Na+ channel Nav1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J. Physiol. 550, 921–926 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Fritch, P. C. et al. Novel KCNQ2/Q3 agonists as potential therapeutics for epilepsy and neuropathic pain. J. Med. Chem. 53, 887–896 (2010).

    CAS  PubMed  Google Scholar 

  36. 36

    Dost, R., Rostock, A. & Rundfeldt, C. The anti-hyperalgesic activity of retigabine is mediated by KCNQ potassium channel activation. Naunyn Schmiedebergs Arch. Pharmacol. 369, 382–390 (2004).

    CAS  PubMed  Google Scholar 

  37. 37

    Lee, S. Pharmacological inhibition of voltage-gated Ca2+ channels for chronic pain relief. Curr. Neuropharmacol. 11, 606–620 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Stemkowski, P. L., Noh, M. C., Chen, Y. & Smith, P. A. Increased excitability of medium-sized dorsal root ganglion neurons by prolonged interleukin-1β exposure is K+ channel dependent and reversible. J. Physiol. 593, 3739–3755 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Zogopoulos, P., Vasileiou, I., Patsouris, E. & Theocharis, S. E. The role of endocannabinoids in pain modulation. Fundam. Clin. Pharmacol. 27, 64–80 (2013).

    CAS  PubMed  Google Scholar 

  40. 40

    Gutenstein, H. & Akil, H. in Goodman and Gilman's Pharmacological Basis of Therapeutics Ch. 21 (eds Brunton, L., Lazo, J. & Parker, K.) 547–590 (The McGraw Hill companies, 2006). Chapter 21 of this authoritative pharmacology text provides a thorough overview of opioid analgesic pharmacology.

    Google Scholar 

  41. 41

    Fries, D. S. in Principles of Medicinal Chemistry Ch. 14 (eds Foye, W. O., Lemke, T. L. & Williams,D. A.) 247–269 (William & Wilkins, 1995). Chapter 14 of this essential medicinal chemistry source describes the medicinal chemistry of common opioid and anti-inflammatory analgesics.

    Google Scholar 

  42. 42

    Lesniak, A. & Lipkowski, A. W. Opioid peptides in peripheral pain control. Acta Neurobiol. Exp. (Wars.) 71, 129–138 (2011).

    Google Scholar 

  43. 43

    Navratilova, E. et al. Positive emotions and brain reward circuits in chronic pain. J. Comp. Neurol. 524, 1646–1652 (2016).

    PubMed  PubMed Central  Google Scholar 

  44. 44

    Navratilova, E. & Porreca, F. Reward and motivation in pain and pain relief. Nat. Neurosci. 17, 1304–1312 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Kolodny, A. et al. The prescription opioid and heroin crisis: a public health approach to an epidemic of addiction. Annu. Rev. Public Health 36, 559–574 (2015).

    PubMed  Google Scholar 

  46. 46

    Cassidy, T. A., DasMahapatra, P., Black, R. A., Wieman, M. S. & Butler, S. F. Changes in prevalence of prescription opioid abuse after introduction of an abuse-deterrent opioid formulation. Pain Med. 15, 440–451 (2014).

    PubMed  Google Scholar 

  47. 47

    Kunins, H. V. Abuse-deterrent opioid formulations: part of a public health strategy to reverse the opioid epidemic. JAMA Intern. Med. 175, 987–988 (2015).

    PubMed  Google Scholar 

  48. 48

    Chilcoat, H. D., Coplan, P. M., Harikrishnan, V. & Alexander, L. Decreased diversion by doctor-shopping for a reformulated extended release oxycodone product (OxyContin). Drug Alcohol Depend. 165, 221–228 (2016).

    PubMed  Google Scholar 

  49. 49

    Coplan, P. M. et al. The effect of an abuse-deterrent opioid formulation on opioid abuse-related outcomes in the post-marketing setting. Clin. Pharmacol. Ther. 100, 275–286 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Cicero, T. J., Ellis, M. S. & Surratt, H. L. Effect of abuse-deterrent formulation of OxyContin. N. Engl. J. Med. 367, 187–189 (2012).

    CAS  PubMed  Google Scholar 

  51. 51

    Cicero, T. J., Ellis, M. S. & Kasper, Z. A. A tale of 2 ADFs: differences in the effectiveness of abuse-deterrent formulations of oxymorphone and oxycodone extended-release drugs. Pain 157, 1232–1238 (2016).

    CAS  PubMed  Google Scholar 

  52. 52

    Walsh, S. L., Strain, E. C., Abreu, M. E. & Bigelow, G. E. Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in humans. Psychopharmacology (Berl.) 157, 151–162 (2001).

    CAS  Google Scholar 

  53. 53

    Pallasch, T. J. & Gill, C. J. Butorphanol and nalbuphine: a pharmacologic comparison. Oral Surg. Oral Med. Oral Pathol. 59, 15–20 (1985).

    CAS  PubMed  Google Scholar 

  54. 54

    Webster, L., Menzaghi, F. & Spencer, R. CR845, a novel peripherally-acting kappa opioid receptor agonist, has low abuse potential compared with pentazocine. J. Pain 16, S81 (2015).

    Google Scholar 

  55. 55

    Spahn, V. et al. A nontoxic pain killer designed by modeling of pathological receptor conformations. Science 355, 966–969 (2017).

    CAS  PubMed  Google Scholar 

  56. 56

    Milligan, G. The prevalence, maintenance, and relevance of G protein-coupled receptor oligomerization. Mol. Pharmacol. 84, 158–169 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Rozenfeld, R. & Devi, L. A. Receptor heteromerization and drug discovery. Trends Pharmacol. Sci. 31, 124–130 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Yekkirala, A. S. Two to tango: GPCR oligomers and GPCR–TRP channel interactions in nociception. Life Sci. 92, 438–445 (2013).

    CAS  PubMed  Google Scholar 

  59. 59

    Yekkirala, A. S., Kalyuzhny, A. E. & Portoghese, P. S. An immunocytochemical-derived correlate for evaluating the bridging of heteromeric mu-delta opioid protomers by bivalent ligands. ACS Chem. Biol. 8, 1412–1416 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Lenard, N. R., Daniels, D. J., Portoghese, P. S. & Roerig, S. C. Absence of conditioned place preference or reinstatement with bivalent ligands containing mu-opioid receptor agonist and delta-opioid receptor antagonist pharmacophores. Eur. J. Pharmacol. 566, 75–82 (2007).

    CAS  PubMed  Google Scholar 

  61. 61

    Aceto, M. D. et al. MDAN-21: a bivalent opioid ligand containing mu-agonist and delta-antagonist pharmacophores and its effects in rhesus monkeys. Int. J. Med. Chem. 2012, 327257 (2012).

    PubMed  PubMed Central  Google Scholar 

  62. 62

    Daniels, D. J. et al. Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series. Proc. Natl Acad. Sci. USA 102, 19208–19213 (2005).

    CAS  PubMed  Google Scholar 

  63. 63

    Le Naour, M. et al. Bivalent ligands that target mu opioid (MOP) and cannabinoid1 (CB1) receptors are potent analgesics devoid of tolerance. J. Med. Chem. 56, 5505–5513 (2013).

    CAS  PubMed  Google Scholar 

  64. 64

    Akgun, E. et al. Ligands that interact with putative MOR-mGluR5 heteromer in mice with inflammatory pain produce potent antinociception. Proc. Natl Acad. Sci. USA 110, 11595–11599 (2013).

    CAS  PubMed  Google Scholar 

  65. 65

    Akgun, E. et al. Inhibition of inflammatory and neuropathic pain by targeting a mu opioid receptor/chemokine receptor5 heteromer (MOR-CCR5). J. Med. Chem. 58, 8647–8657 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Yekkirala, A. S. et al. N-Naphthoyl-beta-naltrexamine (NNTA), a highly selective and potent activator of mu/kappa-opioid heteromers. Proc. Natl Acad. Sci. USA 108, 5098–5103 (2011).

    CAS  PubMed  Google Scholar 

  67. 67

    Chakrabarti, S., Liu, N. J. & Gintzler, A. R. Formation of mu-/kappa-opioid receptor heterodimer is sex-dependent and mediates female-specific opioid analgesia. Proc. Natl Acad. Sci. USA 107, 20115–20119 (2010).

    CAS  PubMed  Google Scholar 

  68. 68

    Ding, H. et al. A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates. Proc. Natl Acad. Sci. USA 113, E5511–E5518 (2016).

    CAS  PubMed  Google Scholar 

  69. 69

    Pasternak, G. W. & Pan, Y. X. Mu opioids and their receptors: evolution of a concept. Pharmacol. Rev. 65, 1257–1317 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Marrone, G. F. et al. Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS. Proc. Natl Acad. Sci. USA 113, 3663–3668 (2016).

    CAS  PubMed  Google Scholar 

  71. 71

    Majumdar, S. et al. Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects. Proc. Natl Acad. Sci. USA 108, 19778–19783 (2011).

    CAS  PubMed  Google Scholar 

  72. 72

    Wieskopf, J. S. et al. Broad-spectrum analgesic efficacy of IBNtxA is mediated by exon 11-associated splice variants of the mu-opioid receptor gene. Pain 155, 2063–2070 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Liu, X. Y. et al. Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell 147, 447–458 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    White, K. L. et al. The G protein-biased kappa-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo. J. Pharmacol. Exp. Ther. 352, 98–109 (2015).

    PubMed  PubMed Central  Google Scholar 

  75. 75

    Tang, W., Strachan, R. T., Lefkowitz, R. J. & Rockman, H. A. Allosteric modulation of beta-arrestin-biased angiotensin II type 1 receptor signaling by membrane stretch. J. Biol. Chem. 289, 28271–28283 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Drake, M. T. et al. β-Arrestin-biased agonism at the β2-adrenergic receptor. J. Biol. Chem. 283, 5669–5676 (2008).

    CAS  PubMed  Google Scholar 

  77. 77

    Wisler, J. W., Xiao, K., Thomsen, A. R. & Lefkowitz, R. J. Recent developments in biased agonism. Curr. Opin. Cell Biol. 27, 18–24 (2014). In this review, the authors describe how different ligands can induce distinct receptor conformations at the same GPCR to elicit unique downstream signalling profiles. They provide support for how these properties could be exploited to develop analgesics with different or reduced side-effect profiles.

    CAS  PubMed  Google Scholar 

  78. 78

    Shukla, A. K. et al. Distinct conformational changes in beta-arrestin report biased agonism at seven-transmembrane receptors. Proc. Natl Acad. Sci. USA 105, 9988–9993 (2008).

    CAS  PubMed  Google Scholar 

  79. 79

    Whalen, E. J., Rajagopal, S. & Lefkowitz, R. J. Therapeutic potential of beta-arrestin- and G protein-biased agonists. Trends Mol. Med. 17, 126–139 (2011).

    CAS  PubMed  Google Scholar 

  80. 80

    Zidar, D. A., Violin, J. D., Whalen, E. J. & Lefkowitz, R. J. Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands. Proc. Natl Acad. Sci. USA 106, 9649–9654 (2009).

    CAS  PubMed  Google Scholar 

  81. 81

    Gesty-Palmer, D. et al. A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation. Sci. Transl Med. 1, 1ra1 (2009).

    PubMed  PubMed Central  Google Scholar 

  82. 82

    Strachan, R. T. et al. Divergent transducer-specific molecular efficacies generate biased agonism at a G protein-coupled receptor (GPCR). J. Biol. Chem. 289, 14211–14224 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Violin, J. D., Crombie, A. L., Soergel, D. G. & Lark, M. W. Biased ligands at G-protein-coupled receptors: promise and progress. Trends Pharmacol. Sci. 35, 308–316 (2014).

    CAS  PubMed  Google Scholar 

  84. 84

    Soergel, D. G. et al. Biased agonism of the mu-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: a randomized, double-blind, placebo-controlled, crossover study in healthy volunteers. Pain 155, 1829–1835 (2014).

    CAS  PubMed  Google Scholar 

  85. 85

    Soergel, D. G. et al. First clinical experience with TRV130: pharmacokinetics and pharmacodynamics in healthy volunteers. J. Clin. Pharmacol. 54, 351–357 (2014).

    CAS  PubMed  Google Scholar 

  86. 86

    Manglik, A. et al. Structure-based discovery of opioid analgesics with reduced side effects. Nature 537, 185–190 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Tabrizi, M. A., Baraldi, P. G., Borea, P. A. & Varani, K. Medicinal chemistry, pharmacology, and potential therapeutic benefits of cannabinoid CB2 receptor agonists. Chem. Rev. 116, 519–560 (2016).

    Google Scholar 

  88. 88

    Han, S., Thatte, J., Buzard, D. J. & Jones, R. M. Therapeutic utility of cannabinoid receptor type 2 (CB2) selective agonists. J. Med. Chem. 56, 8224–8256 (2013).

    CAS  PubMed  Google Scholar 

  89. 89

    Nevalainen, T. Recent development of CB2 selective and peripheral CB1/CB2 cannabinoid receptor ligands. Curr. Med. Chem. 21, 187–203 (2014).

    CAS  PubMed  Google Scholar 

  90. 90

    Anand, U. et al. Mechanisms underlying clinical efficacy of angiotensin II type 2 receptor (AT2R) antagonist EMA401 in neuropathic pain: clinical tissue and in vitro studies. Mol. Pain 11, 38 (2015).

    PubMed  PubMed Central  Google Scholar 

  91. 91

    Danser, A. H. & Anand, P. The angiotensin II type 2 receptor for pain control. Cell 157, 1504–1506 (2014).

    CAS  PubMed  Google Scholar 

  92. 92

    Rice, A. S. et al. EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial. Lancet 383, 1637–1647 (2014).

    CAS  PubMed  Google Scholar 

  93. 93

    Anand, U. et al. Angiotensin II type 2 receptor (AT2 R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons. Eur. J. Pain 17, 1012–1026 (2013).

    CAS  PubMed  Google Scholar 

  94. 94

    Smith, M. T., Woodruff, T. M., Wyse, B. D., Muralidharan, A. & Walther, T. A small molecule angiotensin II type 2 receptor (AT2R) antagonist produces analgesia in a rat model of neuropathic pain by inhibition of p38 mitogen-activated protein kinase (MAPK) and p44/p42 MAPK activation in the dorsal root ganglia. Pain Med. 14, 1557–1568 (2013).

    PubMed  Google Scholar 

  95. 95

    Marion, E. et al. Mycobacterial toxin induces analgesia in buruli ulcer by targeting the angiotensin pathways. Cell 157, 1565–1576 (2014).

    CAS  PubMed  Google Scholar 

  96. 96

    Lemmens, S., Brone, B., Dooley, D., Hendrix, S. & Geurts, N. Alpha-adrenoceptor modulation in central nervous system trauma: pain, spasms, and paralysis — an unlucky triad. Med. Res. Rev. 35, 653–677 (2015).

    CAS  PubMed  Google Scholar 

  97. 97

    Giovannitti, J. A. Jr, Thoms, S. M. & Crawford, J. J. Alpha-2 adrenergic receptor agonists: a review of current clinical applications. Anesth. Prog. 62, 31–39 (2015).

    PubMed  PubMed Central  Google Scholar 

  98. 98

    Mori, K. et al. Effects of norepinephrine on rat cultured microglial cells that express alpha1, alpha2, beta1 and beta2 adrenergic receptors. Neuropharmacology 43, 1026–1034 (2002).

    CAS  PubMed  Google Scholar 

  99. 99

    Lavand'homme, P. M. & Eisenach, J. C. Perioperative administration of the alpha2-adrenoceptor agonist clonidine at the site of nerve injury reduces the development of mechanical hypersensitivity and modulates local cytokine expression. Pain 105, 247–254 (2003).

    CAS  PubMed  Google Scholar 

  100. 100

    Feng, X. et al. Intrathecal administration of clonidine attenuates spinal neuroimmune activation in a rat model of neuropathic pain with existing hyperalgesia. Eur. J. Pharmacol. 614, 38–43 (2009).

    CAS  PubMed  Google Scholar 

  101. 101

    Wei, H. & Pertovaara, A. Spinal and pontine alpha2-adrenoceptors have opposite effects on pain-related behavior in the neuropathic rat. Eur. J. Pharmacol. 551, 41–49 (2006).

    CAS  PubMed  Google Scholar 

  102. 102

    Schnabel, A., Meyer-Friessem, C. H., Reichl, S. U., Zahn, P. K. & Pogatzki-Zahn, E. M. Is intraoperative dexmedetomidine a new option for postoperative pain treatment? A meta-analysis of randomized controlled trials. Pain 154, 1140–1149 (2013).

    CAS  PubMed  Google Scholar 

  103. 103

    Schnabel, A. et al. Efficacy and safety of intraoperative dexmedetomidine for acute postoperative pain in children: a meta-analysis of randomized controlled trials. Paediatr. Anaesth. 23, 170–179 (2013).

    PubMed  Google Scholar 

  104. 104

    Melik Parsadaniantz, S., Rivat, C., Rostene, W. & Reaux-Le Goazigo, A. Opioid and chemokine receptor crosstalk: a promising target for pain therapy? Nat. Rev. Neurosci. 16, 69–78 (2015).

    PubMed  Google Scholar 

  105. 105

    Abbadie, C. et al. Chemokines and pain mechanisms. Brain Res. Rev. 60, 125–134 (2009).

    CAS  PubMed  Google Scholar 

  106. 106

    Reaux-Le Goazigo, A., Van Steenwinckel, J., Rostene, W. & Melik Parsadaniantz, S. Current status of chemokines in the adult CNS. Prog. Neurobiol. 104, 67–92 (2013).

    CAS  PubMed  Google Scholar 

  107. 107

    Van Steenwinckel, J. et al. CCL2 released from neuronal synaptic vesicles in the spinal cord is a major mediator of local inflammation and pain after peripheral nerve injury. J. Neurosci. 31, 5865–5875 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Xie, F., Wang, Y., Li, X., Chao, Y. C. & Yue, Y. Early repeated administration of CXCR4 antagonist AMD3100 dose-dependently improves neuropathic pain in rats after L5 spinal nerve ligation. Neurochem. Res. 41, 2289–2299 (2016).

    CAS  PubMed  Google Scholar 

  109. 109

    Talbot, S., Foster, S. L. & Woolf, C. J. Neuroimmunity: physiology and pathology. Annu. Rev. Immunol. 34, 421–447 (2016).

    CAS  PubMed  Google Scholar 

  110. 110

    Szabo, I. et al. Heterologous desensitization of opioid receptors by chemokines inhibits chemotaxis and enhances the perception of pain. Proc. Natl Acad. Sci. USA 99, 10276–10281 (2002).

    CAS  PubMed  Google Scholar 

  111. 111

    Szabo, I. et al. Selective inactivation of CCR5 and decreased infectivity of R5 HIV-1 strains mediated by opioid-induced heterologous desensitization. J. Leukoc. Biol. 74, 1074–1082 (2003).

    CAS  PubMed  Google Scholar 

  112. 112

    Grimm, M. C. et al. Opiates transdeactivate chemokine receptors: delta and mu opiate receptor-mediated heterologous desensitization. J. Exp. Med. 188, 317–325 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Pello, O. M. et al. Ligand stabilization of CXCR4/delta-opioid receptor heterodimers reveals a mechanism for immune response regulation. Eur. J. Immunol. 38, 537–549 (2008).

    CAS  PubMed  Google Scholar 

  114. 114

    Rivat, C. et al. Src family kinases involved in CXCL12-induced loss of acute morphine analgesia. Brain Behav. Immun. 38, 38–52 (2014).

    CAS  PubMed  Google Scholar 

  115. 115

    Zhao, C. M. et al. Spinal MCP-1 contributes to the development of morphine antinociceptive tolerance in rats. Am. J. Med. Sci. 344, 473–479 (2012).

    PubMed  Google Scholar 

  116. 116

    Zhang, N., Rogers, T. J., Caterina, M. & Oppenheim, J. J. Proinflammatory chemokines, such as C-C chemokine ligand 3, desensitize mu-opioid receptors on dorsal root ganglia neurons. J. Immunol. 173, 594–599 (2004).

    CAS  PubMed  Google Scholar 

  117. 117

    Ye, D. et al. Activation of CXCL10/CXCR3 signaling attenuates morphine analgesia: involvement of Gi protein. J. Mol. Neurosci. 53, 571–579 (2014).

    CAS  PubMed  Google Scholar 

  118. 118

    Rittner, H. L. et al. Pain control by CXCR2 ligands through Ca2+-regulated release of opioid peptides from polymorphonuclear cells. FASEB J. 20, 2627–2629 (2006).

    CAS  PubMed  Google Scholar 

  119. 119

    Wilson, N. M., Jung, H., Ripsch, M. S., Miller, R. J. & White, F. A. CXCR4 signaling mediates morphine-induced tactile hyperalgesia. Brain Behav. Immun. 25, 565–573 (2011).

    CAS  PubMed  Google Scholar 

  120. 120

    Kalliomaki, J. et al. A randomized, double-blind, placebo-controlled trial of a chemokine receptor 2 (CCR2) antagonist in posttraumatic neuralgia. Pain 154, 761–767 (2013).

    PubMed  Google Scholar 

  121. 121

    Padi, S. S. et al. Attenuation of rodent neuropathic pain by an orally active peptide, RAP-103, which potently blocks CCR2- and CCR5-mediated monocyte chemotaxis and inflammation. Pain 153, 95–106 (2012).

    CAS  PubMed  Google Scholar 

  122. 122

    Szallasi, A., Cortright, D. N., Blum, C. A. & Eid, S. R. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat. Rev. Drug Discov. 6, 357–372 (2007).

    CAS  PubMed  Google Scholar 

  123. 123

    Habib, A. M., Wood, J. N. & Cox, J. J. Sodium channels and pain. Handb. Exp. Pharmacol. 227, 39–56 (2015).

    CAS  PubMed  Google Scholar 

  124. 124

    Waxman, S. G. et al. Sodium channel genes in pain-related disorders: phenotype-genotype associations and recommendations for clinical use. Lancet Neurol. 13, 1152–1160 (2014).

    CAS  PubMed  Google Scholar 

  125. 125

    Caterina, M. J. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997).

    CAS  PubMed  Google Scholar 

  126. 126

    Nilius, B. & Szallasi, A. Transient receptor potential channels as drug targets: from the science of basic research to the art of medicine. Pharmacol. Rev. 66, 676–814 (2014).

    PubMed  Google Scholar 

  127. 127

    Moran, M. M., McAlexander, M. A., Biro, T. & Szallasi, A. Transient receptor potential channels as therapeutic targets. Nat. Rev. Drug Discov. 10, 601–620 (2011).

    CAS  PubMed  Google Scholar 

  128. 128

    Carnevale, V. & Rohacs, T. TRPV1: a target for rational drug design. Pharmaceuticals (Basel) 9, E52 (2016).

    Google Scholar 

  129. 129

    Lehto, S. G. et al. Antihyperalgesic effects of (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluorom ethyl)phenyl)-acrylamide (AMG8562), a novel transient receptor potential vanilloid type 1 modulator that does not cause hyperthermia in rats. J. Pharmacol. Exp. Ther. 326, 218–229 (2008).

    CAS  PubMed  Google Scholar 

  130. 130

    Watabiki, T. et al. Amelioration of neuropathic pain by novel transient receptor potential vanilloid 1 antagonist AS1928370 in rats without hyperthermic effect. J. Pharmacol. Exp. Ther. 336, 743–750 (2011).

    CAS  PubMed  Google Scholar 

  131. 131

    Chiche, D., Brown, W. & Walker, P. NEO6860, a novel modality selective TRPV1 antagonist: results from a phase I, double-blind, placebo-controlled study in healthy subjects. J. Pain 17, S79 (2016).

    Google Scholar 

  132. 132

    Gao, Y., Cao, E., Julius, D. & Cheng, Y. TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action. Nature 534, 347–351 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Cao, L. et al. Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia. Sci. Transl Med. 8, 335ra56 (2016).

    PubMed  Google Scholar 

  134. 134

    Dib-Hajj, S. D., Yang, Y., Black, J. A. & Waxman, S. G. The NaV1.7 sodium channel: from molecule to man. Nat. Rev. Neurosci. 14, 49–62 (2013).

    CAS  PubMed  Google Scholar 

  135. 135

    Cox, J. J. et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 444, 894–898 (2006).

    CAS  PubMed  Google Scholar 

  136. 136

    Cox, J. J. et al. Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations. Hum. Mut. 31, E1670–E1686 (2010).

    CAS  PubMed  Google Scholar 

  137. 137

    Nassar, M. A. et al. Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc. Natl Acad. Sci. USA 101, 12706–12711 (2004).

    CAS  PubMed  Google Scholar 

  138. 138

    Minett, M. S. et al. Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons. Nat. Commun. 3, 791 (2012).

    PubMed  PubMed Central  Google Scholar 

  139. 139

    Gingras, J. et al. Global Nav1.7 knockout mice recapitulate the phenotype of human congenital indifference to pain. PLoS ONE 9, e105895 (2014).

    PubMed  PubMed Central  Google Scholar 

  140. 140

    Bagal, S. K., Marron, B. E., Owen, R. M., Storer, R. I. & Swain, N. A. Voltage gated sodium channels as drug discovery targets. Channels (Austin) 9, 360–366 (2015).

    Google Scholar 

  141. 141

    Sun, S., Cohen, C. J. & Dehnhardt, C. M. Inhibitors of voltage-gated sodium channel Nav1.7: patent applications since 2010. Pharm. Pat. Anal. 3, 509–521 (2014).

    CAS  PubMed  Google Scholar 

  142. 142

    Focken, T. et al. Discovery of aryl sulfonamides as isoform-selective inhibitors of NaV1.7 with efficacy in rodent pain models. ACS Med. Chem. Lett. 7, 277–282 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    McCormack, K. et al. Voltage sensor interaction site for selective small molecule inhibitors of voltage-gated sodium channels. Proc. Natl Acad. Sci. USA 110, E2724–E2732 (2013).

    CAS  PubMed  Google Scholar 

  144. 144

    Butt, M. et al. Morphologic, stereologic, and morphometric evaluation of the nervous system in young cynomolgus monkeys (Macaca fascicularis) following maternal administration of tanezumab, a monoclonal antibody to nerve growth factor. Toxicol. Sci. 142, 463–476 (2014).

    CAS  PubMed  Google Scholar 

  145. 145

    Wainger, B. J. et al. Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts. Nat. Neurosci. 18, 17–24 (2015).

    CAS  PubMed  Google Scholar 

  146. 146

    Talbot, S. et al. Silencing nociceptor neurons reduces allergic airway inflammation. Neuron 87, 341–354 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Bauer, C. S. et al. The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin. J. Neurosci. 29, 4076–4088 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Lawrence, J. Nav1.7: a new channel for pain treatment. Pharm. J. (2016).

  149. 149

    Bowman, C. J. et al. Developmental toxicity assessment of tanezumab, an anti-nerve growth factor monoclonal antibody, in cynomolgus monkeys (Macaca fascicularis). Reprod. Toxicol. 53, 105–118 (2015).

    CAS  PubMed  Google Scholar 

  150. 150

    Murray, J. K. et al. Single residue substitutions that confer voltage-gated sodium ion channel subtype selectivity in the NaV1.7 inhibitory peptide GpTx-1. J. Med. Chem. 59, 2704–2717 (2016).

    CAS  PubMed  Google Scholar 

  151. 151

    Weiss, J. et al. Loss-of-function mutations in sodium channel Nav1.7 cause anosmia. Nature 472, 186–190 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Minett, M. S. et al. Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7. Nat. Commun. 6, 8967 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Kort, M. E. et al. Subtype-selective NaV1.8 sodium channel blockers: identification of potent, orally active nicotinamide derivatives. Bioorg. Med. Chem. Lett. 20, 6812–6815 (2010).

    CAS  PubMed  Google Scholar 

  154. 154

    Bagal, S. K. et al. Recent progress in sodium channel modulators for pain. Bioorg. Med. Chem. Lett. 24, 3690–3699 (2014).

    CAS  PubMed  Google Scholar 

  155. 155

    Wilson, M. J. et al. μ-Conotoxins that differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve. Proc. Natl Acad. Sci. USA 108, 10302–10307 (2011).

    CAS  PubMed  Google Scholar 

  156. 156

    Rush, A. M., Cummins, T. R. & Waxman, S. G. Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. J. Physiol. 579, 1–14 (2007).

    CAS  PubMed  Google Scholar 

  157. 157

    Dib-Hajj, S. D., Black, J. A. & Waxman, S. G. NaV1.9: a sodium channel linked to human pain. Nat. Rev. Neurosci. 16, 511–519 (2015).

    CAS  PubMed  Google Scholar 

  158. 158

    Goral, R. O., Leipold, E., Nematian-Ardestani, E. & Heinemann, S. H. Heterologous expression of NaV1.9 chimeras in various cell systems. Pflugers Arch. 467, 2423–2435 (2015).

    CAS  PubMed  Google Scholar 

  159. 159

    Owsianik, G., Talavera, K., Voets, T. & Nilius, B. Permeation and selectivity of TRP channels. Annu. Rev. Physiol. 68, 685–717 (2006).

    CAS  PubMed  Google Scholar 

  160. 160

    Hellwig, N. et al. TRPV1 acts as proton channel to induce acidification in nociceptive neurons. J. Biol. Chem. 279, 34553–34561 (2004).

    CAS  PubMed  Google Scholar 

  161. 161

    Meyers, J. R. et al. Lighting up the senses: FM1-43 loading of sensory cells through nonselective ion channels. J. Neurosci. 23, 4054–4065 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Binshtok, A. M., Bean, B. P. & Woolf, C. J. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 449, 607–610 (2007).

    CAS  PubMed  Google Scholar 

  163. 163

    Puopolo, M. et al. Permeation and block of TRPV1 channels by the cationic lidocaine derivative QX-314. J. Neurophysiol. 109, 1704–1712 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Brenneis, C. et al. Bupivacaine-induced cellular entry of QX-314 and its contribution to differential nerve block. Br. J. Pharmacol. 171, 438–451 (2014).

    CAS  PubMed  Google Scholar 

  165. 165

    Virginio, C., MacKenzie, A., Rassendren, F. A., North, R. A. & Surprenant, A. Pore dilation of neuronal P2X receptor channels. Nat. Neurosci. 2, 315–321 (1999).

    CAS  PubMed  Google Scholar 

  166. 166

    Khakh, B. S., Bao, X. R., Labarca, C. & Lester, H. A. Neuronal P2X transmitter-gated cation channels change their ion selectivity in seconds. Nat. Neurosci. 2, 322–330 (1999).

    CAS  PubMed  Google Scholar 

  167. 167

    Yan, Z., Li, S., Liang, Z., Tomic, M. & Stojilkovic, S. S. The P2X7 receptor channel pore dilates under physiological ion conditions. J. Gen. Physiol. 132, 563–573 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    Binshtok, A. M. et al. Coapplication of lidocaine and the permanently charged sodium channel blocker QX-314 produces a long-lasting nociceptive blockade in rodents. Anesthesiology 111, 127–137 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    Roberson, D. P., Binshtok, A. M., Blasl, F., Bean, B. P. & Woolf, C. J. Targeting of sodium channel blockers into nociceptors to produce long-duration analgesia: a systematic study and review. Br. J. Pharmacol. 164, 48–58 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170

    Leffler, A. et al. The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons. J. Clin. Invest. 118, 763–776 (2008).

    PubMed  PubMed Central  Google Scholar 

  171. 171

    Leffler, A., Lattrell, A., Kronewald, S., Niedermirtl, F. & Nau, C. Activation of TRPA1 by membrane permeable local anesthetics. Mol. Pain 7, 62 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172

    Roberson, D. P. et al. Activity-dependent silencing reveals functionally distinct itch-generating sensory neurons. Nat. Neurosci. 16, 910–918 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173

    Zamponi, G. W., Striessnig, J., Koschak, A. & Dolphin, A. C. The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacol. Rev. 67, 821–870 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    Zamponi, G. W. Targeting voltage-gated calcium channels in neurological and psychiatric diseases. Nat. Rev. Drug Discov. 15, 19–34 (2016). In this Review, Zamponi discusses various challenges and opportunities for using calcium channels as drug targets for neurological disorders.

    CAS  PubMed  Google Scholar 

  175. 175

    Abbadie, C. et al. Analgesic effects of a substituted N-triazole oxindole (TROX-1), a state-dependent, voltage-gated calcium channel 2 blocker. J. Pharmacol. Exp. Ther. 334, 545–555 (2010).

    CAS  PubMed  Google Scholar 

  176. 176

    Patel, R. et al. Electrophysiological characterization of activation state-dependent CaV2 channel antagonist TROX-1 in spinal nerve injured rats. Neuroscience 297, 47–57 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177

    Shao, P. P. et al. Aminopiperidine sulfonamide Cav2.2 channel inhibitors for the treatment of chronic pain. J. Med. Chem. 55, 9847–9855 (2012).

    CAS  PubMed  Google Scholar 

  178. 178

    Lipscombe, D. & Andrade, A. Calcium channel CaVα1 splice isoforms — tissue specificity and drug action. Curr. Mol. Pharmacol. 8, 22–31 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179

    Bourinet, E. et al. Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception. EMBO J. 24, 315–324 (2005).

    CAS  PubMed  Google Scholar 

  180. 180

    Choi, S. et al. Attenuated pain responses in mice lacking CaV3.2 T-type channels. Genes Brain Behav. 6, 425–431 (2007).

    CAS  PubMed  Google Scholar 

  181. 181

    Jarvis, M. F. et al. A peripherally acting, selective T-type calcium channel blocker, ABT-639, effectively reduces nociceptive and neuropathic pain in rats. Biochem. Pharmacol. 89, 536–544 (2014).

    CAS  PubMed  Google Scholar 

  182. 182

    Wallace, M., Duan, R., Liu, W., Locke, C. & Nothaft, W. A. Randomized, double-blind, placebo-controlled, crossover study of the T-type calcium channel blocker ABT-639 in an intradermal capsaicin experimental pain model in healthy adults. Pain Med. 17, 551–560 (2015).

    PubMed  Google Scholar 

  183. 183

    Ziegler, D., Duan, W. R., An, G., Thomas, J. W. & Nothaft, W. A randomized double-blind, placebo-, and active-controlled study of T-type calcium channel blocker ABT-639 in patients with diabetic peripheral neuropathic pain. Pain 156, 2013–2020 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184

    Francois, A. et al. State-dependent properties of a new T-type calcium channel blocker enhance CaV3.2 selectivity and support analgesic effects. Pain 154, 283–293 (2013).

    CAS  PubMed  Google Scholar 

  185. 185

    Xu, J. et al. A mixed Ca2+ channel blocker, A-1264087, utilizes peripheral and spinal mechanisms to inhibit spinal nociceptive transmission in a rat model of neuropathic pain. J. Neurophysiol. 111, 394–404 (2014).

    CAS  PubMed  Google Scholar 

  186. 186

    Zhu, C. Z. et al. Mechanistic insights into the analgesic efficacy of A-1264087, a novel neuronal Ca2+ channel blocker that reduces nociception in rat preclinical pain models. J. Pain 387, e1–e14 (2014).

    Google Scholar 

  187. 187

    Scott, V. E. et al. A-1048400 is a novel, orally active, state-dependent neuronal calcium channel blocker that produces dose-dependent antinociception without altering hemodynamic function in rats. Biochem. Pharmacol. 83, 406–418 (2012).

    CAS  PubMed  Google Scholar 

  188. 188

    Marsh, B., Acosta, C., Djouhri, L. & Lawson, S. N. Leak K+ channel mRNAs in dorsal root ganglia: relation to inflammation and spontaneous pain behaviour. Mol. Cell. Neurosci. 49, 375–386 (2012).

    CAS  PubMed  Google Scholar 

  189. 189

    Pollema-Mays, S. L., Centeno, M. V., Ashford, C. J., Apkarian, A. V. & Martina, M. Expression of background potassium channels in rat DRG is cell-specific and down-regulated in a neuropathic pain model. Mol. Cell. Neurosci. 57, 1–9 (2013).

    CAS  PubMed  Google Scholar 

  190. 190

    Zheng, Q. et al. Suppression of KCNQ/M (Kv7) potassium channels in dorsal root ganglion neurons contributes to the development of bone cancer pain in a rat model. Pain 154, 434–448 (2013).

    CAS  PubMed  Google Scholar 

  191. 191

    Laumet, G. et al. G9a is essential for epigenetic silencing of K+ channel genes in acute-to-chronic pain transition. Nat. Neurosci. 18, 1746–1755 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192

    Lu, R. et al. Slack channels expressed in sensory neurons control neuropathic pain in mice. J. Neurosci. 35, 1125–1135 (2015).

    PubMed  PubMed Central  Google Scholar 

  193. 193

    Lyu, C. et al. G protein-gated inwardly rectifying potassium channel subunits 1 and 2 are down-regulated in rat dorsal root ganglion neurons and spinal cord after peripheral axotomy. Mol. Pain 11, 44 (2015).

    PubMed  PubMed Central  Google Scholar 

  194. 194

    Maljevic, S. & Lerche, H. Potassium channels: a review of broadening therapeutic possibilities for neurological diseases. J. Neurol. 260, 2201–2211 (2013).

    CAS  PubMed  Google Scholar 

  195. 195

    Tsantoulas, C. & McMahon, S. B. Opening paths to novel analgesics: the role of potassium channels in chronic pain. Trends Neurosci. 37, 146–158 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 196

    Tsantoulas, C. Emerging potassium channel targets for the treatment of pain. Curr. Opin. Support. Palliat. Care 9, 147–154 (2015).

    PubMed  Google Scholar 

  197. 197

    Wickenden, A. D. & McNaughton-Smith, G. Kv7 channels as targets for the treatment of pain. Curr. Pharm. Des. 15, 1773–1798 (2009).

    CAS  PubMed  Google Scholar 

  198. 198

    Wu, Y. J. et al. Discovery of (S,E)-3-(2-fluorophenyl)-N-(1-(3-(pyridin-3-yloxy)phenyl)ethyl)-acrylamide as a potent and efficacious KCNQ2 (Kv7.2) opener for the treatment of neuropathic pain. Bioorg. Med. Chem. Lett. 23, 6188–6191 (2013).

    CAS  PubMed  Google Scholar 

  199. 199

    Zheng, Y. et al. Activation of peripheral KCNQ channels relieves gout pain. Pain 156, 1025–1035 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 200

    Mathie, A. & Veale, E. L. Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain. Pflugers Arch. 467, 931–943 (2015).

    CAS  PubMed  Google Scholar 

  201. 201

    Wang, H. S. et al. KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science 282, 1890–1893 (1998).

    CAS  PubMed  Google Scholar 

  202. 202

    Pan, Z. et al. A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. J. Neurosci. 26, 2599–2613 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. 203

    Cooper, E. C. Made for “anchorin”: Kv7.2/7.3 (KCNQ2/KCNQ3) channels and the modulation of neuronal excitability in vertebrate axons. Semin. Cell Dev. Biol. 22, 185–192 (2011).

    CAS  PubMed  Google Scholar 

  204. 204

    Blackburn-Munro, G. & Jensen, B. S. The anticonvulsant retigabine attenuates nociceptive behaviours in rat models of persistent and neuropathic pain. Eur. J. Pharmacol. 460, 109–116 (2003).

    CAS  PubMed  Google Scholar 

  205. 205

    Li, H. et al. Antinociceptive efficacy of retigabine in the monosodium lodoacetate rat model for osteoarthritis pain. Pharmacology 95, 251–257 (2015).

    CAS  PubMed  Google Scholar 

  206. 206

    Rose, K. et al. Transcriptional repression of the M channel subunit Kv7.2 in chronic nerve injury. Pain 152, 742–754 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. 207

    King, C. H., Lancaster, E., Salomon, D., Peles, E. & Scherer, S. S. Kv7.2 regulates the function of peripheral sensory neurons. J. Comp. Neurol. 522, 3262–3280 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. 208

    King, C. H. & Scherer, S. S. Kv7.5 is the primary Kv7 subunit expressed in C-fibers. J. Comp. Neurol. 520, 1940–1950 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. 209

    Feliciangeli, S., Chatelain, F. C., Bichet, D. & Lesage, F. The family of K2P channels: salient structural and functional properties. J. Physiol. 593, 2587–2603 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. 210

    Busserolles, J., Tsantoulas, C., Eschalier, A. & Lopez Garcia, J. A. Potassium channels in neuropathic pain: advances, challenges, and emerging ideas. Pain 157 (Suppl. 1), S7–S14 (2016).

    PubMed  Google Scholar 

  211. 211

    Devilliers, M. et al. Activation of TREK-1 by morphine results in analgesia without adverse side effects. Nat. Commun. 4, 2941 (2013).

    PubMed  Google Scholar 

  212. 212

    Bagriantsev, S. N. et al. A high-throughput functional screen identifies small molecule regulators of temperature- and mechano-sensitive K2P channels. ACS Chem. Biol. 8, 1841–1851 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. 213

    Rodrigues, N. et al. Synthesis and structure-activity relationship study of substituted caffeate esters as antinociceptive agents modulating the TREK-1 channel. Eur. J. Med. Chem. 75, 391–402 (2014).

    CAS  PubMed  Google Scholar 

  214. 214

    Bocksteins, E. & Snyders, D. J. Electrically silent Kv subunits: their molecular and functional characteristics. Physiology (Bethesda) 27, 73–84 (2012).

    CAS  Google Scholar 

  215. 215

    Bocksteins, E. Kv5, Kv6, Kv8, and Kv9 subunits: no simple silent bystanders. J. Gen. Physiol. 147, 105–125 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. 216

    Tsantoulas, C. et al. Sensory neuron downregulation of the Kv9.1 potassium channel subunit mediates neuropathic pain following nerve injury. J. Neurosci. 32, 17502–17513 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. 217

    Tsantoulas, C. et al. Kv2 dysfunction after peripheral axotomy enhances sensory neuron responsiveness to sustained input. Exp. Neurol. 251, 115–126 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. 218

    Bocksteins, E. et al. Kv2.1 and silent Kv subunits underlie the delayed rectifier K+ current in cultured small mouse DRG neurons. Am. J. Physiol. Cell Physiol. 296, C1271–C1278 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. 219

    Stas, J. I., Bocksteins, E., Labro, A. J. & Snyders, D. J. Modulation of closed-state inactivation in Kv2.1/Kv6.4 heterotetramers as mechanism for 4-AP induced potentiation. PLoS ONE 10, e0141349 (2015).

    PubMed  PubMed Central  Google Scholar 

  220. 220

    Knabl, J. et al. Reversal of pathological pain through specific spinal GABAA receptor subtypes. Nature 451, 330–334 (2008).

    CAS  PubMed  Google Scholar 

  221. 221

    Bonin, R. P. & De Koninck, Y. Restoring ionotropic inhibition as an analgesic strategy. Neurosci Lett. 557, 43–51 (2013).

    CAS  PubMed  Google Scholar 

  222. 222

    Klinger, F. et al. δ subunit-containing GABAA receptors are preferred targets for the centrally acting analgesic flupirtine. Br. J. Pharmacol. 172, 4946–4958 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. 223

    Zeilhofer, H. U., Ralvenius, W. T. & Acuna, M. A. Restoring the spinal pain gate: GABAA receptors as targets for novel analgesics. Adv. Pharmacol. 73, 71–96 (2015).

    CAS  PubMed  Google Scholar 

  224. 224

    Tegeder, I. et al. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat. Med. 12, 1269–1277 (2006).

    CAS  PubMed  Google Scholar 

  225. 225

    Latremoliere, A. et al. Reduction of neuropathic and inflammatory pain through inhibition of the tetrahydrobiopterin pathway. Neuron 86, 1393–1406 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. 226

    Chidley, C., Haruki, H., Pedersen, M. G., Muller, E. & Johnsson, K. A yeast-based screen reveals that sulfasalazine inhibits tetrahydrobiopterin biosynthesis. Nat. Chem. Biol. 7, 375–383 (2011).

    CAS  PubMed  Google Scholar 

  227. 227

    Chandrasekhar, S. et al. Identification and characterization of novel microsomal prostaglandin E synthase-1 inhibitors for analgesia. J. Pharmacol. Exp. Ther. 356, 635–644 (2016).

    CAS  PubMed  Google Scholar 

  228. 228

    Jin, Y. et al. Pharmacodynamic comparison of LY3023703, a novel microsomal prostaglandin E synthase 1 inhibitor, with celecoxib. Clin. Pharmacol. Ther. 99, 274–284 (2016).

    CAS  PubMed  Google Scholar 

  229. 229

    Wagner, K., Yang, J., Inceoglu, B. & Hammock, B. D. Soluble epoxide hydrolase inhibition is antinociceptive in a mouse model of diabetic neuropathy. J. Pain 15, 907–914 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. 230

    Inceoglu, B. et al. Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain. Proc. Natl Acad. Sci. USA 112, 9082–9087 (2015).

    CAS  PubMed  Google Scholar 

  231. 231

    Sisignano, M. et al. 5,6-EET is released upon neuronal activity and induces mechanical pain hypersensitivity via TRPA1 on central afferent terminals. J. Neurosci. 32, 6364–6372 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. 232

    Brenneis, C. et al. Soluble epoxide hydrolase limits mechanical hyperalgesia during inflammation. Mol. Pain 7, 78 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. 233

    Lam, D. K., Dang, D., Zhang, J., Dolan, J. C. & Schmidt, B. L. Novel animal models of acute and chronic cancer pain: a pivotal role for PAR2. J. Neurosci. 32, 14178–14183 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. 234

    Christianson, C. A. et al. Spinal matrix metalloproteinase 3 mediates inflammatory hyperalgesia via a tumor necrosis factor-dependent mechanism. Neuroscience 200, 199–210 (2012).

    CAS  PubMed  Google Scholar 

  235. 235

    Berta, T. et al. Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-alpha secretion. J. Clin. Invest. 124, 1173–1186 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. 236

    Clark, A. K., Grist, J., Al-Kashi, A., Perretti, M. & Malcangio, M. Spinal cathepsin S and fractalkine contribute to chronic pain in the collagen-induced arthritis model. Arthritis Rheum. 64, 2038–2047 (2012).

    CAS  PubMed  Google Scholar 

  237. 237

    Vicuna, L. et al. The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase. Nat. Med. 21, 518–523 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. 238

    Landry, R. P., Jacobs, V. L., Romero-Sandoval, E. A. & DeLeo, J. A. Propentofylline, a CNS glial modulator does not decrease pain in post-herpetic neuralgia patients: in vitro evidence for differential responses in human and rodent microglia and macrophages. Exp. Neurol. 234, 340–350 (2012).

    CAS  PubMed  Google Scholar 

  239. 239

    Ji, R. R. Mitogen-activated protein kinases as potential targets for pain killers. Curr. Opin. Investig. Drugs 5, 71–75 (2004).

    PubMed  Google Scholar 

  240. 240

    Ostenfeld, T. et al. A randomized, placebo-controlled trial of the analgesic efficacy and safety of the p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain from lumbosacral radiculopathy. Clin. J. Pain 31, 283–293 (2015).

    PubMed  Google Scholar 

  241. 241

    Smith, M. T., Wyse, B. D. & Edwards, S. R. Small molecule angiotensin II type 2 receptor (AT2R) antagonists as novel analgesics for neuropathic pain: comparative pharmacokinetics, radioligand binding, and efficacy in rats. Pain Med. 14, 692–705 (2013).

    PubMed  Google Scholar 

  242. 242

    Bevan, S., Quallo, T. & Andersson, D. A. TRPV1. Handb. Exp. Pharmacol. 222, 207–245 (2014).

    CAS  PubMed  Google Scholar 

  243. 243

    Girardin, F. Membrane transporter proteins: a challenge for CNS drug development. Dialogues Clin. Neurosci. 8, 311–321 (2006).

    PubMed  PubMed Central  Google Scholar 

  244. 244

    Huggins, J. P., Smart, T. S., Langman, S., Taylor, L. & Young, T. An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee. Pain 153, 1837–1846 (2012).

    CAS  PubMed  Google Scholar 

  245. 245

    Keith, J. M. et al. Preclinical characterization of the FAAH inhibitor JNJ-42165279. ACS Med. Chem. Lett. 6, 1204–1208 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  246. 246

    Pawsey, S. et al. Safety, tolerability and pharmacokinetics of FAAH inhibitor V158866: a double-blind, randomised, placebo-controlled phase I study in healthy volunteers. Drugs R. D 16, 181–191 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  247. 247

    Cajanus, K. et al. Effect of endocannabinoid degradation on pain: role of FAAH polymorphisms in experimental and postoperative pain in women treated for breast cancer. Pain 157, 361–369 (2016).

    CAS  PubMed  Google Scholar 

  248. 248

    Woolf, C. J., Safieh-Garabedian, B., Ma, Q. P., Crilly, P. & Winter, J. Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity. Neuroscience 62, 327–331 (1994).

    CAS  PubMed  Google Scholar 

  249. 249

    Gimbel, J. S. et al. Long-term safety and effectiveness of tanezumab as treatment for chronic low back pain. Pain 155, 1793–1801 (2014).

    CAS  PubMed  Google Scholar 

  250. 250

    Bramson, C. et al. Exploring the role of tanezumab as a novel treatment for the relief of neuropathic pain. Pain Med. 16, 1163–1176 (2015).

    PubMed  Google Scholar 

  251. 251

    Schnitzer, T. J. & Marks, J. A. A systematic review of the efficacy and general safety of antibodies to NGF in the treatment of OA of the hip or knee. Osteoarthritis Cartilage 23 (Suppl. 1), S8–S17 (2015).

    PubMed  Google Scholar 

  252. 252

    Hochberg, M. C. et al. When is osteonecrosis not osteonecrosis? Adjudication of reported serious adverse joint events in the tanezumab clinical development program. Arthritis Rheumatol. 68, 382–391 (2016).

    CAS  PubMed  Google Scholar 

  253. 253

    Sorge, R. E. et al. Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nat. Methods 11, 629–632 (2014).

    CAS  PubMed  Google Scholar 

  254. 254

    Baron, R. et al. Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles. Pain 158, 261–272 (2016).

    PubMed Central  Google Scholar 

  255. 255

    Mogil, J. S., Davis, K. D. & Derbyshire, S. W. The necessity of animal models in pain research. Pain 151, 12–17 (2010). In this review, Mogil and colleagues describe the crucial role of animal models in the development of clinical analgesics and propose advancements in animal models of pain that could improve the relevance and translatability of preclinical studies.

    PubMed  Google Scholar 

  256. 256

    Whiteside, G. T., Pomonis, J. D. & Kennedy, J. D. An industry perspective on the role and utility of animal models of pain in drug discovery. Neurosci. Lett. 557, 65–72 (2013).

    CAS  PubMed  Google Scholar 

  257. 257

    Hill, R. NK1 (substance P) receptor antagonists — why are they not analgesic in humans? Trends Pharmacol. Sci. 21, 244–246 (2000).

    CAS  PubMed  Google Scholar 

  258. 258

    Sorge, R. E. et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat. Neurosci. 18, 1081–1083 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  259. 259

    Edwards, R. R., Dworkin, R. H., Sullivan, M. D., Turk, D. C. & Wasan, A. D. The role of psychosocial processes in the development and maintenance of chronic pain. J. Pain 17, T70–T92 (2016).

    PubMed  PubMed Central  Google Scholar 

  260. 260

    Smith, S. M. et al. Pain intensity rating training: results from an exploratory study of the ACTTION PROTECCT system. Pain 157, 1056–1064 (2016).

    PubMed  Google Scholar 

  261. 261

    Dodd, S., Dean, O. M., Vian, J. & Berk, M. A. Review of the theoretical and biological understanding of the nocebo and placebo phenomena. Clin. Ther. 39, 469–476 (2017).

    PubMed  Google Scholar 

  262. 262

    Paice, J. A. et al. AAPT diagnostic criteria for chronic cancer pain conditions. J. Pain 18, 233–246 (2017).

    PubMed  Google Scholar 

  263. 263

    Smith, S. M. et al. The potential role of sensory testing, skin biopsy, and functional brain imaging as biomarkers in chronic pain clinical trials: IMMPACT considerations. J. Pain (2017).

  264. 264

    Edwards, R. R. et al. Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations. Pain 157, 1851–1871 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  265. 265

    Viscusi, E. R. et al. A randomized, phase 2 study investigating TRV130, a biased ligand of the mu-opioid receptor, for the intravenous treatment of acute pain. Pain 157, 264–272 (2016).

    CAS  PubMed  Google Scholar 

  266. 266

    Lu, Z. et al. Mediation of opioid analgesia by a truncated 6-transmembrane GPCR. J. Clin. Invest. 125, 2626–2630 (2015).

    PubMed  PubMed Central  Google Scholar 

  267. 267

    Moriconi, A. et al. Targeting the minor pocket of C5aR for the rational design of an oral allosteric inhibitor for inflammatory and neuropathic pain relief. Proc. Natl Acad. Sci. USA 111, 16937–16942 (2014).

    CAS  PubMed  Google Scholar 

  268. 268

    Altun, A. et al. Attenuation of morphine antinociceptive tolerance by cannabinoid CB1 and CB2 receptor antagonists. J. Physiol. Sci. 65, 407–415 (2015).

    CAS  PubMed  Google Scholar 

  269. 269

    Haugh, O., Penman, J., Irving, A. J. & Campbell, V. A. The emerging role of the cannabinoid receptor family in peripheral and neuro-immune interactions. Curr. Drug Targets 17, 1834–1840 (2016).

    CAS  PubMed  Google Scholar 

  270. 270

    Deliu, E. et al. The lysophosphatidylinositol receptor GPR55 modulates pain perception in the periaqueductal gray. Mol. Pharmacol. 88, 265–272 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  271. 271

    Kort, M. E. & Kym, P. R. TRPV1 antagonists: clinical setbacks and prospects for future development. Prog. Med. Chem. 51, 57–70 (2012).

    CAS  PubMed  Google Scholar 

  272. 272

    Manitpisitkul, P. et al. Safety, tolerability and pharmacokinetic and pharmacodynamic learnings from a double-blind, randomized, placebo-controlled, sequential group first-in-human study of the TRPV1 antagonist, JNJ-38893777, in healthy men. Clin. Drug Investig. 35, 353–363 (2015).

    CAS  PubMed  Google Scholar 

  273. 273

    Quiding, H. et al. TRPV1 antagonistic analgesic effect: a randomized study of AZD1386 in pain after third molar extraction. Pain 154, 808–812 (2013).

    CAS  PubMed  Google Scholar 

  274. 274

    De Petrocellis, L. & Moriello, A. S. Modulation of the TRPV1 channel: current clinical trials and recent patents with focus on neurological conditions. Recent Pat. CNS Drug Discov. 8, 180–204 (2013).

    CAS  PubMed  Google Scholar 

  275. 275

    Ghosh, S. et al. Full fatty acid amide hydrolase inhibition combined with partial monoacylglycerol lipase inhibition: augmented and sustained antinociceptive effects with reduced cannabimimetic side effects in mice. J. Pharmacol. Exp. Ther. 354, 111–120 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  276. 276

    Grim, T. W. et al. Combined inhibition of FAAH and COX produces enhanced anti-allodynic effects in mouse neuropathic and inflammatory pain models. Pharmacol. Biochem. Behav. 124, 405–411 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  277. 277

    Starowicz, K. et al. Full inhibition of spinal FAAH leads to TRPV1-mediated analgesic effects in neuropathic rats and possible lipoxygenase-mediated remodeling of anandamide metabolism. PLoS ONE 8, e60040 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  278. 278

    Schlosburg, J. E. et al. Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nat. Neurosci. 13, 1113–1119 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  279. 279

    Luz, J. G. et al. Crystal structures of mPGES-1 inhibitor complexes form a basis for the rational design of potent analgesic and anti-inflammatory therapeutics. J. Med. Chem. 58, 4727–4737 (2015).

    CAS  PubMed  Google Scholar 

  280. 280

    Leclerc, P. et al. Characterization of a human and murine mPGES-1 inhibitor and comparison to mPGES-1 genetic deletion in mouse models of inflammation. Prostaglandins Other Lipid Mediat. 107, 26–34 (2013).

    CAS  PubMed  Google Scholar 

  281. 281

    Sjogren, T. et al. Crystal structure of microsomal prostaglandin E2 synthase provides insight into diversity in the MAPEG superfamily. Proc. Natl Acad. Sci. USA 110, 3806–3811 (2013).

    PubMed  Google Scholar 

  282. 282

    Hellio le Graverand, M. P. et al. A 2-year randomised, double-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor, cindunistat (SD-6010), in patients with symptomatic osteoarthritis of the knee. Ann. Rheum. Dis. 72, 187–195 (2013).

    PubMed  Google Scholar 

  283. 283

    Wozniak, K. M. et al. The orally active glutamate carboxypeptidase II inhibitor E2072 exhibits sustained nerve exposure and attenuates peripheral neuropathy. J. Pharmacol. Exp. Ther. 343, 746–754 (2012).

    CAS  PubMed  Google Scholar 

  284. 284

    Vornov, J. J. et al. Pharmacokinetics and pharmacodynamics of the glutamate carboxypeptidase II inhibitor 2-MPPA show prolonged alleviation of neuropathic pain through an indirect mechanism. J. Pharmacol. Exp. Ther. 346, 406–413 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  285. 285

    Huang, J. L., Chen, X. L., Guo, C. & Wang, Y. X. Contributions of spinal D-amino acid oxidase to bone cancer pain. Amino Acids 43, 1905–1918 (2012).

    CAS  PubMed  Google Scholar 

Download references


The authors acknowledge generous funding support from the following US National Institutes of Health grants: NS039518 and NS038253 (US National Institute of Neurological Disorders and Stroke (NINDS) to C.J.W); NS072040 and NS036855 (NINDS to B.P.B.); and DA041912 (US National Institute on Drug Abuse to A.S.Y.).

Author information



Corresponding authors

Correspondence to Ajay S. Yekkirala or Clifford J. Woolf.

Ethics declarations

Competing interests

A.S.Y and D.P.R. are co-founders of Blue Therapeutics in Allston, Massachusetts, USA, which is focused on developing non-addictive painkillers targeting G-protein-coupled receptor heteromers. A.S.Y. holds a patent on an analgesic agent. B.P.B. is a co-founder of Flex Pharma in Boston, Massachusetts, USA, and co-holds patents on using charged sodium channel blockers for pain relief and other indications. C.J.W is co-founder and scientific advisor to Quartet Medicine in Cambridge, Massachusetts, USA, which is focused on developing treatments for chronic pain and inflammation targeting the tetrahydrobiopterin pathway; he is also a consultant and stock holder for Abide Therapeutics in San Diego, California, USA, and holds several patents related to methods and approaches for studying and treating pain.

Related links

PowerPoint slides



Pharmacological agents or ligands that produce analgesia.


A state in which the drug no longer produces the same effect and a higher dose is therefore needed.


An adaptive state that develops when a pharmacological agent is used repeatedly and leads to withdrawal on cessation of the drug regimen.


Enhanced nociceptive response to a noxious stimulus, leading to greater discomfort than before.


Nociceptive response elicited even to previously non-noxious stimuli.


When an organism shows phenotypic characteristics that reflect a different genotype from its own.

Neuropathic pain

A condition leading to pain due to damage or disease of nervous system tissues.

Central sensitization

A condition of the nervous system in which neurons in the central nervous system are in a state of prolonged increase in excitability and synaptic efficacy, coupled with the loss of inhibitory activity.


A lack of, or insensibility to, pain.


Sensory neuronal responses to noxious or damaging stimuli that attribute the sensation of pain.


A state in which an individual's thoughts, feelings and emotions seem to not belong to them.


Inhibition of sensory neuronal response to noxious stimuli that leads to reduction of pain sensation.

Ligand bias

Occurs when a ligand shows selectivity or preference to a particular signal transduction mechanism for a target receptor. Also called 'functional selectivity'.

Psychotomimetic effects

A state of psychosis of the mind leading to delusions, hallucinations, and so on that are precipitated by a pharmacological agent or ligand.

Post-herpetic neuralgia

Pain caused by nerve damage due to infection with varicella zoster virus.


Symptoms such as anxiety and shaking that develop on cessation of a drug that has been used repeatedly.

Trigeminal neuralgia

A painful condition caused by disease affecting, dysfunction of or damage to the trigeminal nerve.


Loss of the sense of smell.

Allosteric modulators

Ligands that alter the activity of an agonist, antagonist or inverse agonist of a target by binding to a site distinct from the active site.

Phenotypic screens

Unbiased screening strategies in which the functional output is a pre-determined alteration of phenotype.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yekkirala, A., Roberson, D., Bean, B. et al. Breaking barriers to novel analgesic drug development. Nat Rev Drug Discov 16, 545–564 (2017).

Download citation

Further reading


Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing