Modulation Effect Of Sensory Neuron-specific Receptors (SNSR) On Nociception And Morphine Tolerance

The present study investigated the modulation effects of sensory neuron-specific receptor (SNSR) on nociception and morphine tolerance in rats on acut pain, formalin and complete Freund’s adjuvant (CFA) inflammatory pain model. Multitechniques, including behavioral, immunohistochemical and Western blot techniques were used in this case.The consequences of our experiment indicates that:Intrathecal (i.t.) administration of bovine adrenal medulla peptide22(BAM22), an endogenous opioid peptide potently activating opioid receptors and SNSR, produced antinociception on nociceptive thermal stimulus and CFA-evoked inflammatory pain, then evidently decreased the expressions of neuronal nitric oxide synthase (nNOS)-positive cells and calcitonin gene-related peptide (CGRP)-immunoreactivity positive nerve fibers in the spinal cord, respectively, Besides, CGRP-positive cells in dorsal root ganglion (DRG). I.t. administration of (Tyr6)-y2-MSH-6-12(MSH) and bovine adrenal medulla8-22(BAM8-22), two selective SNSR agonists, also could reduce hyperalgesia, nocifensive behaviors and expression of nNOS protein in DRG evoked by intraplantar injection of MSH or CFA, respectively. However, they did not alter withdraw latencies assessed in both paw withdraw and tail flick tests. In CFA-induced inflammatory pain, pretreatment with pertussis toxin (PTX) distinctly declined the baseline of paw withdrawal latency (PWL) at24h, but markedly grew antinociception at24h and prolonged baseline at48h in BAM8-22group. Acute i.t. CTAP, a specific μ opioid receptor antagonist, remarkably enhanced the nociceptive sensibility at24h, but observably lengthened baseline at48h in MSH group. Acute i.t. BAM22induced equipotent thermal antinociception in naive and morphine-tolerant rats while chronic BAM22gradually resulted in hyperalgesia and decrease in the effectiveness of antinociception. Thermal and formalin antinociception were partially dropped and expression of c-Fos-like immunoreactivity (FLI) protein was ascended induced by morphine in BAM22-tolerant rats. In rats made tolerant to morphine, prior administration of BAM22significantly resumed antinociceptive response of morphine and descended expression of FLI protein. Pretreatment or co-treatment with BAM8-22reversed the established morphine tolerance colossally. Intermittent administration of BAM8-22or BAM22with morphine consistently resumed morphine-induced antinociception in morphine tolerant rats, however, they did not alter morphine-induced hyperalgesia. Co-administration of BAM8-22every other day, but not daily, with morphine remarkably attenuated the development of morphine tolerance. Furthermore, persistent co-administration of BAM8-22and AP-5or CLT didn’t weaken antinociceptive effect induced by morphine. Pretreatment with BAM8-22or MSH considerably decreased the expressions of CGRP-and nNOS-positive cells or protein in DRG, and nNOS-positive cells in spinal cord induced by inflammation factor in vitro.These results suggest that SNSR plays an evident antinociceptive influence in inflammatory pain but with no obvious change with acute thermal stimulus in naive rats. Activation of SNSR produced increases morphine antinociception as well as attenuated and reversed morphine tolerance. Gi protein, c-Fos, NO, CGRP and μ receptor are involved in the modulation effect of SNSR on nociception, and NMDA receptor and PKC are involved in the mediation of SNSR on morphine tolerance.