Departments of Medicine and Oral and Maxillofacial Surgery, and Division of Neuroscience, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA, United States.
Departments of Preventative and Restorative Dental Sciences and Oral and Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, CA, United States.
Pain. 2021 Apr 1;162(4):1116-1125. doi: 10.1097/j.pain.0000000000002116.
Intradermal administration of low-molecular-weight hyaluronan (LMWH) in the hind paw induced dose-dependent (0.1, 1, or 10 µg) mechanical hyperalgesia of similar magnitude in male and female rats. However, the duration of LMWH hyperalgesia was greater in females. This sexual dimorphism was eliminated by bilateral ovariectomy and by intrathecal administration of an oligodeoxynucleotide (ODN) antisense to the G-protein-coupled estrogen receptor (GPR30) mRNA in females, indicating estrogen dependence. To assess the receptors at which LMWH acts to induce hyperalgesia, LMWH was administered to groups of male and female rats that had been pretreated with ODN antisense (or mismatch) to the mRNA for 1 of 3 hyaluronan receptors, cluster of differentiation 44 (CD44), toll-like receptor 4, or receptor for hyaluronan-mediated motility (RHAMM). Although LMWH-induced hyperalgesia was attenuated in both male and female rats pretreated with ODN antisense for CD44 and toll-like receptor 4 mRNA, RHAMM antisense pretreatment only attenuated LMWH-induced hyperalgesia in males. Oligodeoxynucleotide antisense for RHAMM, however, attenuated LMWH-induced hyperalgesia in female rats treated with ODN antisense to GPR30, as well as in ovariectomized females. Low-molecular-weight hyaluronan-induced hyperalgesia was significantly attenuated by pretreatment with high-molecular-weight hyaluronan (HMWH) in male, but not in female rats. After gonadectomy or treatment with ODN antisense to GPR30 expression in females, HMWH produced similar attenuation of LMWH-induced hyperalgesia to that seen in males. These experiments identify nociceptors at which LMWH acts to produce mechanical hyperalgesia, establishes estrogen dependence in the role of RHAMM in female rats, and establishes estrogen dependence in the inhibition of LMWH-induced hyperalgesia by HMWH.
皮内给予低分子量透明质酸（LMWH）可诱导雄性和雌性大鼠的机械性痛觉过敏（0.1、1 或 10μg）呈剂量依赖性，但 LMWH 痛觉过敏的持续时间在雌性大鼠中更长。双侧卵巢切除术和鞘内给予 G 蛋白偶联雌激素受体（GPR30）mRNA 的反义寡核苷酸（ODN）可消除这种性别二态性，表明雌激素依赖性。为了评估 LMWH 作用于诱导痛觉过敏的受体，将 LMWH 给予已用 ODN 反义（或错配）预处理的雄性和雌性大鼠组，该 ODN 反义针对 3 种透明质酸受体中的 1 种，即 CD44、Toll 样受体 4 或透明质酸介导的运动受体（RHAMM）的 mRNA。尽管预处理 CD44 和 Toll 样受体 4 mRNA 的 ODN 反义可减轻 LMWH 诱导的雄性和雌性大鼠的痛觉过敏，但 RHAMM 反义预处理仅减轻雄性大鼠的 LMWH 诱导的痛觉过敏。然而，用 GPR30 的 ODN 反义预处理的雌性大鼠以及卵巢切除的雌性大鼠中，RHAMM 的 ODN 反义可减轻 LMWH 诱导的痛觉过敏。在雄性大鼠中，高分子量透明质酸（HMWH）预处理可显著减轻 LMWH 诱导的痛觉过敏，但在雌性大鼠中则不然。在雌性大鼠进行性腺切除术或 GPR30 表达的 ODN 反义处理后，HMWH 对 LMWH 诱导的痛觉过敏的抑制作用与雄性大鼠相似。这些实验确定了 LMWH 作用于产生机械性痛觉过敏的伤害感受器，确立了 RHAMM 在雌性大鼠中的作用中的雌激素依赖性，并确立了 HMWH 抑制 LMWH 诱导的痛觉过敏的雌激素依赖性。
