Orphanin FQ produces gender-specific modulation of trigeminal nociception: behavioral and electrophysiological observations.

The present study aimed to determine if orphanin FQ, an endogenous ligand for the opioid receptor like-1 receptor, produces gender-specific effects in the modulation of N-methyl-D-aspartate (NMDA)-evoked responses of trigeminal nociceptive neurons, and in the NMDA-induced nociceptive behavior. Single-unit extracellular recordings were made from nociceptive-specific and wide dynamic range neurons in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in anesthetized (1.5 g/kg urethane) rats. In the proestrous female, orphanin FQ applied microiontophoretically produced facilitation of the NMDA-evoked responses in 50% (16/32) of nociceptive neurons, inhibition in 31% (10/32), and biphasic effects in 19% (6/32). In contrast, in the male, it inhibited the responses in 86% (18/21), and facilitated the responses in 14% (4/21). In ovariectomized animals, orphanin FQ inhibited the responses in 75% (9/12) of nociceptive neurons, facilitated the responses in 17% (2/12) and produced biphasic effects in 8% (1/12). In contrast, in estradiol-treated ovariectomized rats, it facilitated the responses in 46% (5/11), inhibited the responses in 36% (4/11) and produced biphasic effects in 18% (2/11). For behavioral studies, NMDA-induced scratching behavior was used to assess the effects of orphanin FQ. Twenty-eight male, ovariectomized and estradiol-treated ovariectomized rats were microinjected with NMDA (2 nmol in 10 microl) alone through a cannula implanted in the medullary region, while another 27 rats were microinjected with orphanin FQ (10 nmol in 10 microl) 10 min prior to giving NMDA. Orphanin FQ reduced the NMDA-induced nociceptive scratching behavior by 92% in the male, and by 96% in ovariectomized rats. In contrast, in estradiol-treated ovariectomized animals, orphanin FQ facilitated the NMDA-induced scratching behavior by 210%. We conclude from these studies that orphanin FQ is primarily pronociceptive in the female and primarily antinociceptive in the male. Furthermore, we suggest that estrogen is involved in generating the gender-specific effects of orphanin FQ.