Morphine-Conditioned Placebo Analgesia in Female and Male Rats with Chronic Neuropathic Pain: c-Fos Expression in the Rostral Ventromedial Medulla.

Placebo analgesia has great potential to overcome the inadequacies of current drug therapies to treat conditions of chronic pain. The rostral ventromedial medulla (RVM) has been implicated as a critical relay in the antinociceptive pathway underpinning placebo analgesia in humans. We developed a model of opiate-conditioned placebo analgesia in rats with neuropathic injury to identify medullary nuclei active during placebo analgesia. Using female and male rats the degree of thermal allodynia was first determined following nerve injury, and a pharmacological conditioning procedure, pairing contextual cues with the experience of morphine-induced analgesia, was used to elicit placebo analgesic reactions. This protocol revealed clear subpopulations of placebo reactors (36% of males, 25% of females) and non-reactors in proportions similar to those reported in human studies. We detected injury-specific c-Fos expression in the gracile nucleus and morphine-specific c-Fos expression in the serotonergic midline raphe nuclei and the caudal nuclei of the solitary tract. However, c-Fos expression did not differ between placebo reactors and non-reactors in either serotonergic or non-serotonergic neurons of the RVM. Despite a subpopulation of rats demonstrating placebo reactions, we found no evidence for enhanced activity in the nuclei from which the classical RVM → spinal cord descending analgesic pathways emerge.