Comparison of the antinociceptive response to morphine and morphine-like compounds in male and female Sprague-Dawley rats

Male rats are more sensitive to the antinociceptive effects of morphine than female rats. This difference is seen across several rat strains using a variety of nociceptive stimuli. However, the literature in regard to sex differences in antinociceptive responses to mu-opioids other than morphine is less consistent. The present study was designed to examine whether there is a structure-activity rationale that determines which mu-opioids will show a differential antinociceptive response between male and female rats. A series of morphinans closely related in structure to morphine, namely, codeine, heroin, hydrocodone, hydromorphone, oxymorphone, and oxycodone, were examined for their antinociceptive activity in male and female Sprague-Dawley rats and compared with the structurally unrelated mu-opioid agonists methadone and fentanyl. Antinociception was measured by the warm-water tail-withdrawal assay. The results show that morphine is more potent in males compared with females > hydromorphone = hydrocodone = oxymorphone, but there was no observable sex difference in the antinociceptive potency of codeine, heroin, oxycodone, methadone, or fentanyl. The potency to stimulate guanosine 5'O-(3[S-35]thio) triphosphate ([S-35]GTP gamma S) binding and binding affinity of the various morphinans was compared in rat glioma C6 cells expressing the rat mu-opioid receptor; relative efficacy was also compared by stimulation of [S-35]GTP gamma S binding in slices of rat brain thalamus. The presence of a sex difference in antinociceptive responsiveness was not related to drug potency, efficacy, or affinity. Consequently, it is likely that differential metabolism of the opioid, possibly by glucuronidation, determines the presence or absence of a sex difference.