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

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.Opiate drugs, the prototype of which is morphine, are used largely for the treatment of severe pain. However, the prolonged use of opiate drugs induces a behavioral adaptation that results in the development of tolerance and dependence 1 . Although these adaptive mechanisms have been known for decades, the underlying pathophysiological pathways have not been fully clarified. It has been proposed that the opioid receptor signaling pathway is adaptively regulated at the cellular level, although more recently a growing contribution of the plasticity of neuronal networks involving opioidergic neurons has been recognized. In support of this latter hypothesis, a number of neuropeptides, including cholecystokinin (CCK) 2 , neuropeptide FF (NPFF) 3 and nociceptin (orphanin FQ) 4 , have been proposed as modulators of the opioid system. These various peptidergic pathways are collectively designated as an anti-opioid system. However, the action of individual peptides on the opioid pathway and on the processing of nociceptive signals is complex and some aspects remain controversial, particularly as the behavioral consequences can vary depending on the injection site of these peptides and the precise experimental setup 5,6 . Among these peptides, NPFF, which belongs to the RF-amide peptide family, was shown (among other actions) to regulate blood pressure 7 , prolactin release 8 and nociceptive signal processing 9 . Prolactin-releasing peptide (PrRP) has recently been identified as an additional member of the mammalian RF-amide peptide family, following its isolation as the natural agonist of the previously orphan GPR10 (ref. 10) (also known as hGR3 in human or UHR-1 in rat). Intracerebroventricular (i.c.v.) administration of PrRP affects feeding behavior 11 , blood pressure 12 and neuroendocrine processes, such as corticotropin-releasing hormone (CRH) 13 and oxytocin 14 release.In a...

Endogenous prolactin-releasing peptide regulates food intake in rodents

“…PrRP is expressed in subpopulations of neurons in the NTS, the ventrolateral medulla, and the dorsomedial hypothalamus and has been implicated in several physiological processes (24,25), including satiety signaling (10)(11)(12)(13)22), stress-induced release of ACTH and oxytocin (16,19,26,27), and nociception (20). In the present study, most of the PrRP neurons in the NTS were activated after initiation of food intake, with no significant activation of PrRP neurons in the hypothalamus.…”

“…In the medulla oblongata, PrRP is exclusively colocalized in noradrenergic neurons (6). PrRP has been suggested to be involved in energy metabolism (10)(11)(12)(13)(14)(15), stress responses (16)(17)(18)(19), and analgesia (20).…”

Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway

“…GPR10 has central functions in stress hormone release and feeding behavior (16,(33)(34)(35). It is now widely accepted that, whereas the ligand PrRP is expressed in the periphery, normal function of the receptor GPR10 is limited to various parts of the brain (16,36).…”

The role of RFamide peptides in feeding

“…05 reduces the sensitivity of normal rats to mechanical pressure (paw pinch; Kalliomaki et al 2004). Furthermore, mice lacking GPR10 exhibit higher nociceptive thresholds and stronger stress-induced analgesia than wild-type mice (Laurent et al 2005). Fish and chicken orthologues to mammalian PrRP have been identified , Seale et al 2002, Tachibana et al 2005.…”