• antinociception;
  • dorsal horn;
  • noradrenergic;
  • pain;
  • trigeminal


This is the first demonstration of sex-related differences in the α2-adrenoceptor-mediated antinociceptive effects produced by stimulation of an endogenous noradrenergic pathway. Electrical or chemical (substance P) stimulation of Kölliker–Fuse nucleus (KF, A7) is known to produce antinociception mediated by α2-adrenoceptors in the spinal cord. KF stimulation has also been shown to inhibit the responses of nociceptive neurons in the dorsal horn of the medulla and the spinal cord. We investigated whether KF stimulation produces sex-specific modulation of trigeminal nociception. The N-methyl-d-aspartic acid (NMDA)-induced nociceptive behavior was employed as an index of nociception. Microinjection of NMDA (2 nmol/10 µL) in the trigeminal region produced nociceptive scratching behavior that was confined to the orofacial region. Male and ovariectomized (OVX) Sprague–Dawley rats were implanted with a guide cannula dorsal to the KF nucleus and a PE-10 cannula in the trigeminal region dorsal to obex. Nociceptive testing was conducted after 5–7 days of recovery. A group of ovariectomized rats (OVX+E) was treated with estradiol benzoate 48 h prior to nociceptive testing. There were no significant differences in the number of NMDA-induced scratches or duration between the male, OVX and OVX+E groups. Microinjection of substance P (3.7 pmol/0.5 µL) in the KF significantly reduced the number of NMDA-induced scratches and their duration in male and OVX groups; these were restored to control levels by yohimbine (30 µg/15 µL), an α2-adrenoceptor antagonist. However, KF stimulation failed to inhibit the NMDA-induced scratching behavior in the OVX+E group. We conclude that stimulation of KF produces estrogen-dependent modulation of nociception.