Fig. 8.

Putative molecular mechanism underlying sustained morphine-mediated sensitization of capsaicin evoked CGRP release in primary sensory neurons. Stimulation of the opioid receptor (OR) by an opioid agonist (morphine) in the primary sensory DRG neurons liberates G protein βγ subunits. The free G protein βγ subunits interact with multiple effectors, leading to the activation of Raf-1 through multiple parallel pathways (Varga et al., 2003a). Activated Raf-1 phosphorylates and sensitizes adenylyl cyclase VI (AC VI), leading to up-regulation of cAMP (cAMP overshoot). Increased cAMP activity leads to increased activation of cAMP-dependent protein kinase (PKA). PKA phosphorylates TRPV1 channels, increasing the efficacy of capsaicin to stimulate calcium influx into the sensory neurons, leading to augmented pain neurotransmitter (CGRP) release. The putative molecular targets of the inhibitors used in the present work are indicated in the figure. GW5074 is a selective Raf-1 inhibitor, whereas H-89 and PKI are nonselective and selective PKA inhibitors, respectively.