Melanocortin 4 receptor antagonists attenuates morphine antinociceptive tolerance, astroglial activation and cytokines expression in the spinal cord of rat.

Chronic use of morphine is accompanied by the development of morphine tolerance, which is one of the major problems associated with opiate treatment. Experimental evidence indicates that melanocortin 4 receptor (MC4R) is involved in development of morphine tolerance. Therefore, we investigated the influence of repeated intrathecal injection of a MC4R antagonist (HS014) on the development of morphine tolerance as measured by hot-plate test. It was also examined whether a single i.t. HS014 administration could counteract the loss of analgesic potency of morphine in morphine tolerant rats. We examined also the influence of i.t. HS014 administration on astrocytes activation and cytokines expression in the spinal cord of rat during morphine tolerance. Morphine treatment (10mg/kg, i.p. twice daily) over 5 days induced tolerance as reflected by a significant reduction of withdrawal latency from 29.67±1.81s to 8.67±1.70s in the hot-plate test. Repeated coadministration of HS014 and morphine, significantly prevented the development of morphine tolerance. A single administration of an MC4R antagonist restored morphine analgesic potency in morphine tolerant rats. Using immunohistochemical staining, we demonstrated the administration of MC4R during the induction of morphine tolerance inhibited the activation of astrocytes; reduced the expression of proinflammatory cytokines interleukin-1β, IL-6, and tumor necrosis factor-α; upregulated the expression of anti-inflammatory cytokines IL-10 at the L5 lumbar spinal cord. These results suggest that MC4R may be involved in the mechanisms of morphine tolerance and antagonists of this receptor may be a possible new target in the search for strategies preventing the development of morphine tolerance.