Inhibiting the breakdown of endogenous opioids and cannabinoids to alleviate pain

Key Points

  • The endogenous opioid system is involved in key physiological functions such as pain and mood control. It is often assisted in these functions by the endogenous cannabinoid system, which appeared much later in evolution. The primary endogenous effectors of these systems are enkephalins and anandamide (AEA), respectively.

  • Increasing the concentrations and half-life of enkephalins and AEA, and thereby enhancing the functions of the endogenous opioid system and the endogenous cannabinoid system, respectively, is the core concept that led to the development of the novel analgesics and mood regulators described in this Review.

  • Exogenous effectors — such as morphine — that indiscriminately overstimulate all central and peripheral opioid receptors may induce serious unwanted effects such as constipation, respiratory depression, tolerance or dependence.

  • The tonic release of enkephalins occurs only in a limited number of structures involved in pain control, in areas where the noxious stimulus takes place: in nociceptors (which are located at the periphery), in the medulla or in the brain. Therefore, enhancing enkephalin concentrations does not induce the side effects observed with morphine.

  • Increasing the concentrations and half-life of enkephalins by inhibiting both of the zinc metallopeptidases (enkephalinases) that account for their rapid degradation has analgesic effects that are comparable to those of morphine. Similarly, the protection of endogenous cannabinoids from degradation by fatty acid amide hydrolase (FAAH) elicits analgesic effects.

  • Dual enkephalinase (DENK) inhibitors that are capable of concomitantly inhibiting both enkephalinases at nanomolar concentrations have been designed based on their structures and using molecular modelling. Similarly, irreversible inhibitors of FAAH have been designed.

  • Analgesia produced by DENK inhibitors and FAAH inhibitors represents the first new strategy to alleviate pain that has reached clinical development in decades.

  • The leading DENK inhibitor, PL37, which is entering Phase II clinical trials, has been shown to act at the peripheral level in animal models of neuropathic pain as well as in individuals with neuropathic pain; therefore, considering its favourable safety profile, PL37 is a candidate for the treatment of neuropathic pain.

  • All current treatments for pain potentiate the analgesic properties of DENK inhibitors, especially on neuropathic pain. In addition, DENK inhibitors have shown promising antidepressant effects in animal models.

Abstract

Chronic pain remains unsatisfactorily treated, and few novel painkillers have reached the market in the past century. Increasing the levels of the main endogenous opioid peptides — enkephalins — by inhibiting their two inactivating ectopeptidases, neprilysin and aminopeptidase N, has analgesic effects in various models of inflammatory and neuropathic pain. Stemming from the same pharmacological concept, fatty acid amide hydrolase (FAAH) inhibitors have also been found to have analgesic effects in pain models by preventing the breakdown of endogenous cannabinoids. Dual enkephalinase inhibitors and FAAH inhibitors are now in early-stage clinical trials. In this Review, we compare the effects of these two potential classes of novel analgesics and describe the progress in their rational design. We also consider the challenges in their clinical development and opportunities for combination therapies.

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Figure 1: Endogenous opioid and endogenous cannabinoid signalling: differences in synthesis, secretion mechanisms and metabolism.
Figure 2: Endogenous opioids and endogenous cannabinoids are present at all three levels of pain control.
Figure 3: Main selective dual NEP–APN inhibitors.
Figure 4: Main FAAH inhibitors.

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Acknowledgements

The authors wish to thank A. Bouju for her help in preparing the manuscript.

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Correspondence to Bernard P. Roques.

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B.P.R is Chief Scientific Officer at Pharmaleads SAS.

M.C.F.Z. is Director of the Chemistry Department at Pharmaleads SAS.

M.W. is Director of Corporate Development at Pharmaleads SAS.

Glossary

Fibromyalgia

A disorder of unknown aetiology that is characterized by widespread pain, abnormal pain processing, sleep disturbance, fatigue and often psychological distress.

Neuropathic pain

Pain caused by a lesion or a disease of the somatosensory nervous system.

Chronic constrictive injury model

An animal model of mononeuropathic pain in rodents resulting from ligation of the sciatic nerve, which induces a painful syndrome analogous to that observed in humans. Chronic constrictive injury models may differ according to the location and the tightness of the ligation along the sciatic nerve.

Mononeuropathic rats

Rats that mimic the symptoms induced by nerve injury in humans. Symptoms are restricted to the area innervated by the injured nerve.

Isobolographic plot

A method of determining drug synergy. The theoretical additive ED50 value (the half-maximal effective dose) is estimated from the dose–response curves of each drug administered individually. This theoretical ED50 value is compared with the experimental ED50 value. If a statistically significant difference is observed, synergy is present.

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Roques, B., Fournié-Zaluski, MC. & Wurm, M. Inhibiting the breakdown of endogenous opioids and cannabinoids to alleviate pain. Nat Rev Drug Discov 11, 292–310 (2012). https://doi.org/10.1038/nrd3673

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