PERIPHERAL AND CENTRAL CONTRIBUTIONS TO THE PERSISTENT EXPRESSION OF SPINAL-CORD FOS-LIKE IMMUNOREACTIVITY PRODUCED BY SCIATIC-NERVE TRANSECTION IN THE RAT

Previous studies have demonstrated that noxious stimuli, intense enough to produce tissue injury, evoke a transient expression of the Fos protein product of the c-fos proto-oncogene in neurons, in regions of the spinal cord that contribute to the transmission of nociceptive messages in the rat. Since there is evidence that increases in fos-like immunoreactivity reflect increases in neuronal activity, it has thus been possible to identify populations of neurons that are activated in response to tissue injury. In this study we used immunocytochemical localization of fos-like immunoreactive (FLI) neurons to map the patterns of neuronal activity in the spinal cord at different times after peripheral nerve injury in the rat. Sciatic nerve transection induced a persistent (at least 1 month) elevation in the number of FLI neurons, predominantly in laminae 1, 2, 5, 6 and 7 of the ipsilateral lumbar enlargement of the spinal cord. In the L5 segment, the expression of fos-like immunoreactivity in the superficial dorsal horn (laminae 1 and 2) fluctuated, with peaks of Fos expression at 2 h, 2 days and 2 weeks after nerve transection. Furthermore, by 2 weeks after nerve injury, the distribution of labelled neurons in the superficial laminae of the dorsal horn shifted, with the most densely labelled cells now located in the central portion of the superficial dorsal horn. In contrast, the pattern of labelled neurons in laminae 5, 6 and 7 was relatively constant over the 4-week study period. Local anesthetic block of the sciatic nerve significantly decreased the number of FLI neurons when it was administered at either 2 days or 2 weeks post nerve injury. At 2 days, injection of the local anesthetic subcutaneously in the dorsum of neck, to control for a systemic action, also reduced expression of FLI in laminae 1 and 2; at 2 weeks, the systemic injection of the local anesthetic reduced expression of FLI throughout the gray matter of the spinal cord. These results demonstrate that peripheral nerve injury, in contrast to tissue injury, induces a prolonged increase in Fos expression in neurons predominantly in those regions of the spinal cord that are associated with the transmission of nociceptive messages. This pattern of fos-like immunoreactivity is probably the result of persistent neuronal activity in the spinal cord. The increased 'activity' in the spinal cord appears to be maintained both by abnormal activity in the injured peripheral nerve as well as by reorganization of circuits within the spinal cord secondary to the nerve injury.