Involvement of NMDA receptor in nociceptive effects elicited by intrathecal [Tyr6] gamma2-MSH(6-12), and the interaction with nociceptin/orphanin FQ in pain modulation in mice.

The mas-related genes (Mrgs, also known as sensory neuron-specific receptors, SNSRs) are specifically expressed in small diameter sensory neurons in the trigeminal and dorsal root ganglia, suggesting an important role of the receptors in pain transmission. The present study aimed to investigate the underlying mechanism of the nociceptive effects after activation of MrgC, and the interaction between MrgC and N/OFQ-NOP receptor system in modulation of nociception in mice. Intrathecal (i.t.) administration of [Tyr(6)] gamma2-MSH(6-12), the most potent agonist for MrgC receptor, produced a significant hyperalgesic response as assayed by tail withdrawal test and a series of characteristic nociceptive responses, including biting, licking and scratching, in a dose-dependent manner (0.01-10 pmol and 0.01-10 nmol, respectively) in mice. These pronociceptive effects induced by [Tyr(6)] gamma2-MSH(6-12) were inhibited dose-dependently by co-injection of competitive NMDA receptor antagonist D-APV, non-competitive NMDA receptor antagonist MK-801, and nitric oxide (NO) synthase inhibitor L-NAME. However, the tachykinin NK(1) receptor antagonist L-703,606, and tachykinin NK(2) receptor antagonist MEN-10,376, had no influence on pronociceptive effects elicited by [Tyr(6)] gamma2-MSH(6-12). In other groups, [Tyr(6)] gamma2-MSH(6-12)-induced nociceptive responses were bidirectionally regulated by the co-injection of N/OFQ. N/OFQ inhibited nociceptive responses at high doses (0.01-1 nmol), but potentiated the behaviors at low doses (1 fmol-3 pmol). Furthermore, both hyperalgesia and nociceptive responses were enhanced after the co-administration with NOP receptor antagonist [Nphe(1)]N/OFQ(1-13)-NH(2). These results suggest that intrathecal [Tyr(6)] gamma2-MSH(6-12)-induced pronociceptive effects may be mediated through NMDA receptor-NO system in the spinal cord, and demonstrate the interaction between MrgC and N/OFQ-NOP receptor system in pain transmission.

Neuropeptide S produces antinociceptive effects at the supraspinal level in mice.

Neuropeptide S (NPS), a recently identified bioactive peptide through reverse pharmacology approach, was reported to regulate arousal, anxiety, locomotor activity, feeding behaviors and drug reward. NPS receptor (NPSR) mRNA was found in the area related to the descending control system of pain, such as the periaqueductal gray (PAG), raphe nuclei, and lateral parabrachial nucleus (PBN), suggesting a possible role of the NPS-NPSR system in the regulation of pain transmission. In the present study, we evaluated the effects of NPS in pain modulation at the supraspinal level for the first time, using the tail withdrawal test and hot-plate test in mice. NPS (mouse, 0.01-1 nmol) injected intracerebroventricularly (i.c.v.) caused a significant increase of tail withdrawal latency and paw-licking/jumping latency in the tail withdrawal test and the hot-plate test, respectively. Antinociceptive effect elicited by NPS (0.1 nmol, i.c.v.) was not affected by naloxone (i.c.v., 10 nmol co-injection or i.p., 10 mg/kg, 10 min prior to NPS) in both tail withdrawal test and hot-plate test. However, at the doses, naloxone significantly inhibited the antinociceptive effect induced by morphine (i.c.v., 3 nmol). NPS (0.1 nmol, i.c.v.)-induced antinociception was inhibited by co-injection with 10 nmol, but not 3 nmol [D-Cys(tBu)(5)]NPS, a peptidergic antagonist identified more recently, while [D-Cys(tBu)(5)]NPS (3 and 10 nmol) alone induced neither hyperalgesia nor antinociception. These results revealed that NPS could produce antinociception through NPS receptor, but not opioid receptor, and NPS-NPSR system could be a potential target for developing new analgesic drugs.

Neuropeptide S inhibits the acquisition and the expression of conditioned place preference to morphine in mice.

Neuropeptide S (NPS), a recently identified bioactive peptide, was reported to regulate arousal, anxiety, motoring and feeding behaviors. NPS precursor and NPS receptor mRNA were found in the amygdala, the ventral tegmental area (VTA) and the substantia nigra, the area thought to modulate rewarding properties of drugs. In the present study, we examined the influence of NPS on the rewarding action of morphine, using the unbiased conditioned place preference (CPP) paradigm. Morphine (1, 3 and 6 nmol, i.c.v.) induced a significant place preference. For testing the effect of NPS on the acquisition of morphine CPP, mice were given the combination of NPS and morphine on the conditioning days, and without drug treatment on the followed test day. To study the effect of NPS on the expression of morphine CPP, mice received the treatment of saline/morphine on the conditioning days, and NPS on the test day, 15 min before the placement in the CPP apparatus. Our results showed that NPS (0.3-10 nmol) alone neither induced place preference nor aversion, however, NPS (1 and 3 nmol) blocked the acquisition of CPP induced by 3 nmol morphine, and acquisition of 6 nmol morphine-induced CPP was also reduced by NPS (6 and 10 nmol). Moreover, the expression of CPP induced by 6 nmol morphine was also inhibited by NPS (0.1, 1 and 10 nmol). These results revealed the involvement of NPS in rewarding activities of morphine, and demonstrated the interaction between NPS system and opioid system for the first time.