The Studies On The Antinociceptive Effect Of NPS; The Pain-Modulating Roles Of [Tyr~6]γ2-MSH(6-12) At The Spinal Level

Partâ… : The studies on the antinociceptive effect ofneuropeptide SNeuropeptide S (NPS), a recently identified bioactive peptide, was reported toregulate arousal, anxiety, motoring and feeding behaviors. NPS receptor (NPSR)mRNA was found in the area related to descending control system of pain, such as theperiaqueductal gray (PAG), raphe nuclei, and lateral parabrachial nucleus (PBN),suggesting the possible role of NPS-NPSR system in the regulation of paintransmission. In the present study, we evaluated the effects of NPS in pain modulationat the supraspinal level for the first time, using tail withdrawal test and hot-plate test inmice. NPS (mouse, 0.01-1 nmol) injected intracerebroventricularly (i.c.v.) caused asignificant increase of tail withdrawal latency and paw-licking/jumping latency in thetail withdrawal test and the hot-plate test, respectively. Antinociceptive effect elicitedby NPS (0.1 nmol, i.c.v.) was not affected by naloxone (i.c.v., 10 nmol co-injection ori.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 effectinduced by morphine (i.c.v., 3 nmol). NPS (0.1 nmol, i.c.v.)-induced antinociceptionwas inhibited by co-injection with 10 nmol, but not 3 nmol [D-Cys(tBu)⁵]NPS, apeptidergic antagonist identified more recently, while [D-Cys(tBu)⁵]NPS (3 and 10nmol) alone induced neither hyperalgesia nor antinociception. These results revealedthat 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.Partâ…¡: The pain-modulating roles of [Tyr⁶]γ2-MSH(6-12) at the spinal levelThe mas-related genes (Mrgs, also known as sensory neuron-specific receptors,SNSRs) are specific expressed in small diameter sensory neurons in the trigeminal anddorsal root ganglia, suggesting an important role of the receptors in pain transmission.The present study aimed to investigate the underlying mechanism of the nociceptiveeffects after activation of MrgC, and the interaction between MrgC and N/OFQ-NOPreceptor system in modulation of nociception in mice. Intrathecal (i.t.) administrationof [Tyr⁶]γ2-MSH(6-12), the most potent agonist for MrgC receptor, produced asignificant hyperalgesic response as assayed by tail-withdrawal test and a series ofcharacteristic nociceptive responses, including biting, licking and scratching, in adose-dependent manner (0.01-10pmol and 0.01-10nmol, respectively) in mice. These pronociceptive effects induced by [Tyr⁶]γ2-MSH(6-12) were inhibiteddose-dependently by co-injection of competitive NMDA receptor antagonist D-APV,non-competitive NMDA receptor antagonist MK-801, and nitric oxide (NO)synthaseinhibitor L-NAME. However, the tachykinin NK₁ receptor antagonist L-703,606, andtachykinin NK₂ receptor antagonist MEN-10,376. had no influence on pronociceptiveeffects elicited by [Tyr⁶]γ2-MSH(6-12).In other groups, [Tyr⁶]γ2-MSH(6-12)-induced nociceptive responses werebidirectionally regulated by the co-injection of N/OFQ. N/OFQ inhibited nociceptiveresponses at high doses (0.01-1 nmol), but potentiated the behaviors at low doses (1fmol-3 pmol). Furthermore, both hyperalgesia and nociceptive responses wereenhanced after the co-administration with NOP receptor antagonist[Nphe¹]N/OFQ(1-13)-NH₂.These results suggest that intrathecal [Tyr⁶]γ2-MSH(6-12)-induced pronociceptiveeffects may be mediated through NMDA receptor-NO system in the spinal cord, anddemonstrate the interaction between MrgC and N/OFQ-NOP receptor system in paintransmission.