Cell-type specific activation of p38 and ERK mediates calcitonin gene-related peptide involvement in tolerance to morphine-induced analgesia.

Tolerance to morphine-induced analgesia is a well-established phenomenon, often limiting its usefulness in the long-term treatment of pain. The mechanisms underlying tolerance are not well understood. We previously suggested a possible role for spinal calcitonin gene-related peptide (CGRP) in the development of tolerance to morphine-induced analgesia. In the present study, we demonstrate that CGRP is involved in morphine tolerance by differentially regulating the ERK-dependent up-regulation of IL-1beta, TNF-alpha, and microsomal prostaglandin E synthase-1 (mPGES-1) in astrocytes and p38-dependent up-regulation of IL-6 in microglia in the rat spinal cord. A 7-d treatment with morphine induced tolerance to the antinociceptive effect and increased phosphorylated ERK localized in astrocytes and phosphorylated p38 enriched in microglia, both effects being inhibited by blocking CGRP receptors. Interestingly, the inhibition of the ERK pathway suppressed the development of tolerance and morphine-induced up-regulation of IL-1beta, TNF-alpha, and mPGES-1. Blockade of p38 activity also inhibited the development of tolerance and morphine-induced IL-6 up-regulation. Taken together, these data suggest that chronic morphine induces the synthesis of CGRP, which in turn acts on CGRP receptors located on astrocytes and microglia to stimulate ERK and p38, respectively, leading to increased synthesis and release of proinflammatory mediators resulting in tolerance to morphine-induced analgesia.