Sustained Morphine Treatment Augments Capsaicin-Evoked Calcitonin Gene-Related Peptide Release from Primary Sensory Neurons in a Protein Kinase A- and Raf-1-Dependent Manner

Studies have shown that long-term (5,6)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol (morphine) treatment in-creases the sensitivity to painful heat stimuli (thermal hyperal-gesia). The cellular adaptations contributing to sustained morphine-mediated pain sensitization are not fully understood. It was shown previously (J Neurosci 22:6747–6755, 2002) that sustained morphine exposure augments pain neurotransmitter [such as calcitonin gene-related peptide (CGRP)] release in the dorsal horn of the spinal cord in response to the heat-sensing transient receptor potential vanilloid 1 receptor agonist 8-methyl-N-vanillyl-6-nonenamide (capsaicin). In the present study, we demonstrate that sustained morphine-mediated aug-mentation of CGRP release from isolated primary sensory dor-sal root ganglion neurons is dependent on protein kinase A and Raf-1 kinase. Our data indicate that, in addition to neural system adaptations, sustained opioid agonist treatment also produces intracellular compensatory adaptations in primary sensory neurons, leading to augmentation of evoked pain neurotransmitter release from these cells. Opioid analgesics such as (5,6)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol (morphine) are widely used in the treatment of various pain conditions. It is interesting, however, that long-term treatment with opioid analgesics paradoxically increases the sensitivity of patients (Koppert, 2004) and experimental animals to mildly painful and nor-mally innocuous thermal stimuli (thermal hyperalgesia and allodynia). It was suggested that such paradoxical pain sensitization may contribute to the development of antinoci-ceptive tolerance (Mao et al., 1995; Vanderah et al., 2000