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The prolactin-releasing peptide antagonizes the opioid system through its receptor GPR10

Nature Neuroscience volume 8, pages 1735–1741 (2005)Cite this article

Abstract

Prolactin-releasing peptide (PrRP) and its receptor G protein–coupled receptor 10 (GPR10) are expressed in brain areas involved in the processing of nociceptive signals. We investigated the role of this new neuropeptidergic system in GPR10-knockout mice. These mice had higher nociceptive thresholds and stronger stress-induced analgesia than wild-type mice, differences that were suppressed by naloxone treatment. In addition, potentiation of morphine-induced antinociception and reduction of morphine tolerance were observed in mutants. Intracerebroventricular administration of PrRP in wild-type mice promoted hyperalgesia and reversed morphine-induced antinociception. PrRP administration had no effect on GPR10-mutant mice, showing that its effects are mediated by GPR10. Anti-opioid effects of neuropeptide FF were found to require a functional PrRP-GPR10 system. Finally, GPR10 deficiency enhanced the acquisition of morphine-induced conditioned place preference and decreased the severity of naloxone-precipitated morphine withdrawal syndrome. Altogether, our data identify the PrRP-GPR10 system as a new and potent negative modulator of the opioid system.

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Figure 1: GPR10 gene targeting.
Figure 2: Activity of the hypothalamus-pituitary-adrenal (HPA) axis.
Figure 3: Nociceptive thresholds in GPR10-knockout mice.
Figure 4: Anti-opiate properties of PrRP, NPFF and nociceptin.
Figure 5: Effects of the PrRP-GPR10 system on morphine tolerance, dependence and rewarding.
Figure 6: Modulation of the opioid and anti-opioid systems.

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References

  1. Inturrisi, C.E. Clinical pharmacology of opioids for pain. Clin. J. Pain 18, S3–13 (2002).

    Article  PubMed  Google Scholar 

  2. Noble, F. & Roques, B.P. CCK-B receptor: chemistry, molecular biology, biochemistry and pharmacology. Prog. Neurobiol. 58, 349–379 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Panula, P. et al. Neuropeptide FF and modulation of pain. Brain Res. 848, 191–196 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Calo, G., Guerrini, R., Rizzi, A., Salvadori, S. & Regoli, D. Pharmacology of nociceptin and its receptor: a novel therapeutic target. Br. J. Pharmacol. 129, 1261–1283 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Meunier, J.C. Utilizing functional genomics to identify new pain treatments: the example of nociceptin. Am. J. Pharmacogenomics 3, 117–130 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Mollereau, C., Roumy, M. & Zajac, J.M. Opioid-modulating peptides: mechanisms of action. Curr. Top. Med. Chem. 5, 341–355 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Allard, M., Labrouche, S., Nosjean, A. & Laguzzi, R. Mechanisms underlying the cardiovascular responses to peripheral administration of NPFF in the rat. J. Pharmacol. Exp. Ther. 274, 577–583 (1995).

    CAS  PubMed  Google Scholar 

  8. Sundblom, D.M., Heikman, P., Naukkarinen, H. & Fyhrquist, F. Blood concentrations of vasopressin, neuropeptide FF and prolactin are increased by high-dose right unilateral ECT. Peptides 20, 319–326 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Roumy, M. & Zajac, J.M. Neuropeptide FF, pain and analgesia. Eur. J. Pharmacol. 345, 1–11 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Hinuma, S. et al. A prolactin-releasing peptide in the brain. Nature 393, 272–276 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Lawrence, C.B., Celsi, F., Brennand, J. & Luckman, S.M. Alternative role for prolactin-releasing peptide in the regulation of food intake. Nat. Neurosci. 3, 645–646 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Samson, W.K., Resch, Z.T. & Murphy, T.C. A novel action of the newly described prolactin-releasing peptides: cardiovascular regulation. Brain Res. 858, 19–25 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Maruyama, M. et al. Prolactin-releasing peptide as a novel stress mediator in the central nervous system. Endocrinology 142, 2032–2038 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Maruyama, M. et al. Central administration of prolactin-releasing peptide stimulates oxytocin release in rats. Neurosci. Lett. 276, 193–196 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Roland, B.L. et al. Anatomical distribution of prolactin-releasing peptide and its receptor suggests additional functions in the central nervous system and periphery. Endocrinology 140, 5736–5745 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Passik, S.D. & Weinreb, H.J. Managing chronic nonmalignant pain: overcoming obstacles to the use of opioids. Adv. Ther. 17, 70–83 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Lin, S.H., Leslie, F.M. & Civelli, O. Neurochemical properties of the prolactin releasing peptide (PrRP) receptor expressing neurons: evidence for a role of PrRP as a regulator of stress and nociception. Brain Res. 952, 15–30 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Kalliomaki, M.L. et al. Prolactin-releasing peptide affects pain, allodynia and autonomic reflexes through medullary mechanisms. Neuropharmacology 46, 412–424 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Mogil, J.S., Sternberg, W.F., Balian, H., Liebeskind, J.C. & Sadowski, B. Opioid and nonopioid swim stress-induced analgesia: a parametric analysis in mice. Physiol. Behav. 59, 123–132 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Semenova, S., Kuzmin, A. & Zvartau, E. Strain differences in the analgesic and reinforcing action of morphine in mice. Pharmacol. Biochem. Behav. 50, 17–21 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Lin, S.H., Leslie, F.M. & Civelli, O. Neurochemical properties of the prolactin releasing peptide (PrRP) receptor expressing neurons: evidence for a role of PrRP as a regulator of stress and nociception. Brain Res. 952, 15–30 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Pacak, K. et al. In vivo hypothalamic release and synthesis of catecholamines in spontaneously hypertensive rats. Hypertension 22, 467–478 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. Lawrence, C.B., Ellacott, K.L. & Luckman, S.M. PRL-releasing peptide reduces food intake and may mediate satiety signaling. Endocrinology 143, 360–367 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Ueda, H., Inoue, M. & Mizuno, K. New approaches to study the development of morphine tolerance and dependence. Life Sci. 74, 313–320 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Solomon, R.L. & Corbit, J.D. An opponent-process theory of motivation. I. Temporal dynamics of affect. Psychol. Rev. 81, 119–145 (1974).

    Article  CAS  PubMed  Google Scholar 

  26. Malin, D.H. et al. FMRF-NH2-like mammalian peptide precipitates opiate-withdrawal syndrome in the rat. Peptides 11, 277–280 (1990).

    Article  CAS  PubMed  Google Scholar 

  27. Panula, P. et al. Neuropeptide FF and modulation of pain. Brain Res. 848, 191–196 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Murphy, N.P., Lee, Y. & Maidment, N.T. Orphanin FQ/nociceptin blocks acquisition of morphine place preference. Brain Res. 832, 168–170 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. King, M.A., Rossi, G.C., Chang, A.H., Williams, L. & Pasternak, G.W. Spinal analgesic activity of orphanin FQ/nociceptin and its fragments. Neurosci. Lett. 223, 113–116 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Ueda, H., Inoue, M., Takeshima, H. & Iwasawa, Y. Enhanced spinal nociceptin receptor expression develops morphine tolerance and dependence. J. Neurosci. 20, 7640–7647 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ueda, H. et al. Partial loss of tolerance liability to morphine analgesia in mice lacking the nociceptin receptor gene. Neurosci. Lett. 237, 136–138 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Noble, F., Derrien, M. & Roques, B.P. Modulation of opioid antinociception by CCK at the supraspinal level: evidence of regulatory mechanisms between CCK and enkephalin systems in the control of pain. Br. J. Pharmacol. 109, 1064–1070 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Noble, F. & Roques, B.P. The role of CCK2 receptors in the homeostasis of the opioid system. Drugs Today (Barc.) 39, 897–908 (2003).

    Article  CAS  Google Scholar 

  34. Pommier, B. et al. Deletion of CCK2 receptor in mice results in an upregulation of the endogenous opioid system. J. Neurosci. 22, 2005–2011 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Langmead, C.J. et al. Characterization of the binding of [(125)I]-human prolactin releasing peptide (PrRP) to GPR10, a novel G protein coupled receptor. Br. J. Pharmacol. 131, 683–688 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Laorden, M.L., Castells, M.T. & Milanes, M.V. Effects of morphine and morphine withdrawal on brainstem neurons innervating hypothalamic nuclei that control the pituitary-adrenocortical axis in rats. Br. J. Pharmacol. 136, 67–75 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dayas, C.V., Buller, K.M., Crane, J.W., Xu, Y. & Day, T.A. Stressor categorization: acute physical and psychological stressors elicit distinctive recruitment patterns in the amygdala and in medullary noradrenergic cell groups. Eur. J. Neurosci. 14, 1143–1152 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Delfs, J.M., Zhu, Y., Druhan, J.P. & Aston-Jones, G. Noradrenaline in the ventral forebrain is critical for opiate withdrawal-induced aversion. Nature 403, 430–434 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Martin, M., Ledent, C., Parmentier, M., Maldonado, R. & Valverde, O. Involvement of CB1 cannabinoid receptors in emotional behaviour. Psychopharmacology (Berl.) 159, 379–387 (2002).

    Article  CAS  Google Scholar 

  40. Simonin, F., Valverde, O., Smadja, C., Slowe, S., Kitchen, I., Dierich, A., Le Meur, M., Roques, B.P., Maldonado, R. & Kieffer, B.L. Disruption of the kappa-opioid receptor gene in mice enhances sensitivity to chemical visceral pain, impairs pharmacological actions of the selective kappa-agonist U-50,488H and attenuates morphine withdrawal. EMBO J. 17, 886–897 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank C. Contet, L. Cuvelier and D. Houtteman for technical assistance and F. Simonin for helpful discussion. M.P. and S.N.S. were supported by the Fondation Médicale Reine Elisabeth and the Fonds de la Recherche Scientifique Médicale. M.P. was also supported by the Belgian 'Interuniversity Attraction Poles' program, initiated by the Belgian State, Prime Minister's Office, Science Policy Programming and the LifeSciHealth (grant LSHB-CT-2003-503337) programs of the European Community. O.V. and R.M. were supported by the Spanish Ministry of Science and Technology (SAF 2001-0745 to O.V. and GEN2003-20651-C06-04 to R.M). P.L. was supported by fellowships from the Fonds pour la Recherche dans l'Industrie et l'Agriculture and Télévie. C.L and A. de K. are Chercheurs Qualifiés of the Fonds National de la Recherche Scientifique. Scientific responsibility is assumed by the authors.

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  1. Patrick Laurent and Jerome A J Becker: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (I.R.I.B.H.M.), Université Libre de Bruxelles, Campus Erasme, Route de Lennik 808, Brussels, Belgium

    Patrick Laurent, Jerome A J Becker, Catherine Ledent, Gilbert Vassart & Marc Parmentier

  2. Laboratori de Neurofarmacologia, Facultat de Ciènces de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain

    Olga Valverde & Rafael Maldonado

  3. Laboratory of Neurophysiology, Université Libre de Bruxelles, Campus Erasme, Route de Lennik 808, Brussels, Belgium

    Alban de Kerchove d'Exaerde & Serge N Schiffmann

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Correspondence to Marc Parmentier.

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Supplementary information

Supplementary Fig. 1

Corticosterone supplementation. (PDF 221 kb)

Supplementary Fig. 2

Lower incidence of somatic signs of withdrawal in KO mice. (PDF 240 kb)

Supplementary Fig. 3

Morphine-induced regulation of NPFF and PrRP transcript levels. (PDF 320 kb)

Supplementary Table 1

[35S]GTPγS binding assay of the μ-opioid receptor. (PDF 26 kb)

Supplementary Methods (PDF 137 kb)

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Laurent, P., Becker, J., Valverde, O. et al. The prolactin-releasing peptide antagonizes the opioid system through its receptor GPR10. Nat Neurosci 8, 1735–1741 (2005). https://doi.org/10.1038/nn1585

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