Sex difference in the nociceptin/orphanin FQ (N/OFQ) system in rat spinal cord following chronic morphine treatment

This study examined the effect of chronic morphine treatment on levels of N/OFQ and levels and activity of the N/OFQ peptide (NOP) receptor. After morphine injection (10–80 mg/kg, s.c) twice daily for five consecutive days, both male and female Wistar rats showed less responsiveness to morphine, with male rats significantly more tolerant to the antinociceptive actions of morphine than females. The N/OFQ content of spinal cord (SC) extracts as measured by radioimmunoassay was not affected by chronic morphine treatment in either sex, although basal levels were higher in females. N/OFQ content in cerebrospinal fluid (CSF) was reduced significantly in male rats with chronic morphine exposure, though levels were also reduced in CSF from female rats. Scatchard analysis of [ 3 H]N/OFQ saturation binding data indicated that NOP receptor affinity decreased only in male rats, whereas the receptor levels increased in both sexes after morphine treatment, this was even more dramatic in males. [ 35 S]GTPγS binding assay showed that chronic morphine increased N/OFQ‐stimulated [ 35 S]GTPγS binding to SC membranes from male rats but not females. Taken together, these findings demonstrate sex differences in expression of N/OFQ, and NOP receptor activity following chronic morphine treatment, as well as extent of morphine tolerance. Supported by NIH R01‐DA017380 and a seed grant from the Presbyterian Health Fund to KMS.