Jeong Younhee, Wagner Monica A, Ploutz-Snyder Robert J, Holden Janean E
College of Nursing Science, Kyung Hee University, 26 Kyunghee-daero, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
The University of Pittsburgh School of Nursing, 3500 Victoria Street, Victoria Bldg, Pittsburgh, PA 15261, United States.
IBRO Rep. 2019 Dec 17;8:11-17. doi: 10.1016/j.ibror.2019.12.003. eCollection 2020 Jun.
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-adrenoceptors mediating antinociception, while pronociceptive α-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- or an α-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-adrenoceptor blockade and hyperalgesia following α-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.
已知外侧下丘脑（LH）在急性伤害感受中通过下行去甲肾上腺素能系统调节伤害感受，但对其在神经性疼痛状态中的作用了解较少。在未受过处理的雌性动物中，LH刺激会产生α - 肾上腺素能受体的相反作用，其中α - 肾上腺素能受体介导抗伤害感受，而伤害感受促进性α - 肾上腺素能受体则会减弱这种作用。在神经性疼痛状态下或未受过处理的雄性动物中是否会出现这种相反反应尚不清楚。我们采用混合因子设计，将慢性缩窄损伤（CCI）的雄性和雌性大鼠与未受过处理的大鼠进行比较，通过对热刺激的总爪撤离（TPW）反应来测量。大鼠接受三种剂量的卡巴胆碱之一以刺激LH，随后鞘内注射α - 或α - 肾上腺素能受体拮抗剂（分别为WB4101或育亨宾）或生理盐水作为对照。总体而言，未受过处理的大鼠比CCI大鼠表现出更明显的α - 肾上腺素能相反反应（p < 0.04）。未受过处理的雄性和雌性大鼠在α - 肾上腺素能受体阻断后表现出抗伤害感受，而在α - 肾上腺素能受体阻断后表现出痛觉过敏。雄性CCI大鼠对WB4101或育亨宾也表现出剂量依赖性效应（p < 0.05），而雌性CCI大鼠对WB4101有显著的抗伤害感受（p < 0.05），但对育亨宾无反应。这些结果支持以下观点：外周神经损伤会以不同方式改变雄性和雌性大鼠的下行去甲肾上腺素能调节系统，值得注意的是，雌性CCI大鼠不会因下行去甲肾上腺素能输入而表现出抗伤害感受。这些发现表明，采用下行去甲肾上腺素能系统的临床治疗可能需要根据患者性别采用不同方法。
