The present study was undertaken to investigate the plasticity of calcitonin gene-related peptide (CGRP) in antinociception after morphine tolerance in rats. The hindpaw withdrawal latencies (HWLs) to both thermal and mechanical stimulation increased significantly after intracerebroventricular injection of 2.5nmol of CGRP in opioid-naive rats, indicating that CGRP produces an antinociceptive effect in the brain. Furthermore, there was an antinociceptive effect after intracerebroventricular injection of 2.5nmol of CGRP in morphine-tolerant rats. Interestingly, the antinociceptive effect induced by intracerebroventricular injection of CGRP was lower in morphine-tolerant rats than that in opioid-naive rats at the same dose. At the same time, there was downregulation of CGRP-like immunoreactivity in both lateral septal nucleus and central nucleus of amygdala tested by immunohistochemical methods, whereas no significant changes were observed in arcuate nucleus of hypothalamus and periaqueductal gray after morphine treatment in rats. The present study demonstrates plastic changes in both CGRP-induced antinociception and CGRP-like immunoreactivity in rat brain after morphine tolerance, suggesting that CGRP may play an important role in morphine tolerance.

The present study investigated the role of calcitonin gene-related peptide (CGRP) in the modulation of nociception in periaqueductal grey (PAG) of rats. Hindpaw withdrawal latencies (HWLs) were tested by hot-plate and Randall Selitto tests. The HWLs to thermal and mechanical stimulation increased significantly after intra-PAG administration of 0.26 or 0.13nmol of CGRP, but not 0.026nmol of CGRP. The anti-nociceptive effects induced by CGRP were significantly blocked by intra-PAG administration of 0.026 or 0.26nmol of the CGRP1 receptor antagonist CGRP8-37. Furthermore, administration of CGRP into the decussation of superior cerebellar peduncle, out of PAG, did not elicit anti-nociceptive effects during 60min after the injection. The results demonstrated that CGRP plays an important role in antinociception in PAG of rats, and CGRP1 receptor is involved in the CGRP-induced anti-nociception.

Recent studies showed that oxytocin and opioid peptides play important roles in pain modulation at different levels in the central nervous system. The present study was performed to explore whether opioid system is involved in the oxytocin-induced antinociception in the brain of rats. The results showed that: (1) intracerebroventricular injection of oxytocin induced dose-dependent increases in hindpaw withdrawal latencies (HWL) to noxious thermal and mechanical stimulation in rats. (2) The antinociceptive effect of oxytocin was attenuated dosedependently by intracerebroventricular injection of naloxone, indicating an involvement of opioid system in the oxytocin-induced antinociception. (3) It is interesting that the antinociceptive effect of oxytocin was attenuated by subsequent intracerebroventricular injection of the μ-opioid antagonist β-funaltrexamine (β-FNA) and the κ-opioid antagonist nor-binaltorphimine (nor-BNI), but not the δ-opioid antagonist naltrindole. The results indicate that oxytocin plays an antinociceptive role in the brain of rats; μ- and κ-opioid receptors, not δ-receptors, are involved in the oxytocin-induced antinociception in the central nervous system of rats.

Neuropeptide nociceptin/orphanin FQ is the endogenous ligand for the opioid-receptor-like receptor 1 (ORL1), mediating essential functions in the central and peripheral nervous systems. The present study was performed to investigate the role of nociceptin and ORL1 receptor in nociception and morphine-induced antinociception in the arcuate nucleus of hypothalamus in rats. Hindpaw withdrawal latencies (HWL) were measured by hot-plate and Randall Selitto tests. The HWL to both thermal and mechanical stimulation decreased significantly after intra-arcuate nucleus injection of nociceptin in a dose-dependent manner. The effect of nociceptin was blocked significantly by subsequent intra-arcuate nucleus administration of [Nphe1] nociceptin (1-13)-NH2, an ORL1 receptor antagonist. Furthermore, an intra-arcuate nucleus injection of nociceptin dramatically attenuated the antinociceptive effect induced by morphine either injected in the same site or applied intraperitoneally. These results suggest that nociceptin in the arcuate nucleus induces a hyperalgesic effect by acting on ORL1 receptors. The present study also demonstrates an interaction between nociceptin and opioids in the arcuate nucleus of the hypothalamus.

The present study was performed in rats with experimentally induced mononeuropathy after left common sciatic nerve ligation. The hindpaw withdrawal latencies to thermal and mechanical stimulation increased significantly after intra-periaqueductal grey injection of 2 or 3nmol, but not 1nmol of galanin in rats with mononeuropathy. Intraperitoneal administration of 4.5mg/kg morphine induced significant increases in hindpaw withdrawal latencies to both noxious stimulation, which were attenuated by following intra-periaqueductal grey injection of 2nmol of the galanin antagonist galantide. Furthermore, the antinociceptive effect induced by intra-periaqueductal grey injection of 26.6nmol of morphine was attenuated significantly by following intra-periaqueductal gray administration of 2nmol of galantide. The results demonstrated that in periaqueductal grey galanin plays an antinociceptive role in rats with mononeuropathy and galanin is involved in the mechanisms of opioid-induced antinociception.