Morphological evidence for the involvement of microglial p38 activation in CGRP-associated development of morphine antinociceptive tolerance.

Calcitonin gene-related peptide (CGRP) exerts an effect on the development of morphine antinociceptive tolerance, which may in part involve the activation of p38 kinase. In the present study, we investigated the temporal expression and spatial distribution of p38 phosphorylation as well as their possible regulation by CGRP receptor signaling following chronic morphine treatment. A 7-day intrathecal treatment with morphine (15 μg/day) produced tolerance to its analgesic effects as well as a rightward shift in the dose-response curve to its antinociceptive effects. This treatment time-dependently increased p38 phosphorylation in the spinal dorsal horn, as shown by phosphorylated p38-immunoreactive (p-p38-ir) cell counts. The increased phosphorylation occurred first in superficial layers of the spinal dorsal horn and then extended to deeper laminae. Interestingly, accompanying the development of morphine tolerance, p-p38-ir cells, identified as microglia, displayed hypertrophy and increased number of branched processes, suggesting their activation. These various behavioral and morphological changes were blocked by the intrathecal treatment with BIBN4096BS, a non-peptide CGRP receptor antagonist. These data provide additional morphological evidence in support of a role for CGRP in the development of morphine antinociceptive tolerance, possibly by regulating the expression and distribution of p38 phosphorylation in microglia.