Formalin-evoked Fos expression in spinal cord is enhanced in morphine-tolerant rats.

It has been hypothesized that tolerance to the analgesic effects of morphine results from the development of a compensatory response in neurons that express the opioid receptor or in neural circuits in which those neurons participate. The compensatory response establishes a sensitized state in these neurons. To determine if administration of a noxious stimulus can unmask a sensitization of dorsal horn neurons in morphine-pelleted rats, we injected morphine-tolerant and control rats with formalin into the plantar surface of the hindpaw, counted the number of flinches for 2 h and then processed the lumbar cord for Fos immunocytochemistry. Although there was no significant difference in flinching behavior between the morphine-tolerant and control groups, we recorded significantly increased total Fos-like immunoreactivity at the L4/5 and L2 segments both ipsilateral and contralateral to the site of formalin injection in the morphine-tolerant rats compared to the control rats. These results suggest that lumbar spinal cord neurons are sensitized during the development of tolerance, that the sensitization can be unmasked by the administration of a noxious stimulus and that it is manifested as increased expression of the Fos protein in the lumbar cord.