Pain condition and sex differences in the descending noradrenergic system following lateral hypothalamic stimulation

The lateral hypothalamus (LH) is known to modulate nociception via the descending noradrenergic system in acute nociception, but less is known about its role in neuropathic pain states. In naïve females, LH stimulation produces opposing effects of α-adrenoceptors, with α(2)-adrenoceptors mediating antinociception, while pronociceptive α(1)-adrenoceptors attenuate the effect. Whether this opposing response is seen in neuropathic conditions or in naïve males is unknown. We used a mixed factorial design to compare male and female rats with chronic constriction injury (CCI) to naïve rats, measured by Total Paw Withdrawal (TPW) responses to a thermal stimulus. Rats received one of three doses of carbachol to stimulate the LH followed by intrathecal injection of either an α(1)- or an α(2)-adrenoceptor antagonist (WB4101 or yohimbine, resp.) or saline for control. Overall, naïve rats showed a more pronounced opposing alpha-adrenergic response than CCI rats (p < 0.04). Naïve male and female rats demonstrated antinociception following α(1)-adrenoceptor blockade and hyperalgesia following α(2)-adrenoceptor blockade. Male CCI rats also showed dose dependent effects from either WB4101 or yohimbine (p < 0.05), while female CCI rats had significant antinociception from WB4101 (p < 0.05), but no effect from yohimbine. These results support the idea that peripheral nerve damage differentially alters the descending noradrenergic modulatory system in male and female rats, and notably, that female CCI rats do not show antinociception from descending noradrenergic input. These findings are suggestive that clinical therapies that recruit the descending noradrenergic system may require a different approach based on patient gender.