Bonet Ivan J M, Araldi Dionéia, Khomula Eugen V, Bogen Oliver, Green Paul G, Levine Jon D
Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California, United States.
Department of Preventative and Restorative Dental Sciences, Division of Neuroscience, University of California at San Francisco, San Francisco, California, United States.
Pain. 2025 Mar 1;166(3):539-556. doi: 10.1097/j.pain.0000000000003419. Epub 2024 Oct 10.
High molecular weight hyaluronan (HMWH) inhibits hyperalgesia induced by diverse pronociceptive inflammatory mediators and their second messengers, in rats of both sexes. However, the hyperalgesia induced by ligands at 3 pattern recognition receptors, lipopolysaccharide (a toll-like receptor 4 agonist), lipoteichoic acid (a toll-like receptor 2/6 agonist), and nigericin (a NOD-like receptor family, pyrin domain containing 3 activator), and oxaliplatin and paclitaxel chemotherapy-induced peripheral neuropathy are only attenuated in males. After gonadectomy or intrathecal administration of an antisense to G-protein-coupled estrogen receptor 30 (GPER) mRNA, HMWH produces antihyperalgesia in females. In nociceptors cultured from rats that had been treated with oxaliplatin, HMWH reverses nociceptor sensitization from male and GPER antisense-treated female, but not from gonad intact females. G-protein-coupled estrogen receptor-dependent sex dimorphism for HMWH-induced antihyperalgesia was also observed for the prolongation of prostaglandin E 2 (PGE 2 )-induced hyperalgesia in primed nociceptors. While in primed rats, HMWH inhibits early, protein kinase A-dependent hyperalgesia, 30 minutes post PGE 2 injection, in both sexes; measured 4 hours post-PGE 2 , HMWH inhibits the protein kinase Cε (PKCε)-dependent prolongation of PGE 2 hyperalgesia only in males and GPER antisense-treated females. In females, hyperalgesia induced by PKCε agonist, ψεRACK, in control but not in primed nociceptors, was inhibited by HMWH. Inhibitors of 2 GPER second messengers, extracellular-regulated kinase 1/2 and nonreceptor tyrosine kinase, also unmasked HMWH antihyperalgesia in females with oxaliplatin chemotherapy-induced peripheral neuropathy, a condition in which nociceptors are primed as well as sensitized. Our results support GPER-dependent sex dimorphism in HMWH-induced antihyperalgesia for pain induced by pattern recognition receptor agonists, and chronic inflammatory and neuropathic pain, mediated by changes in signaling downstream of PKCε in primed nociceptors.
高分子量透明质酸（HMWH）可抑制由多种伤害感受性炎症介质及其第二信使诱导的痛觉过敏，在雌雄大鼠中均有此作用。然而，由3种模式识别受体的配体（脂多糖，一种Toll样受体4激动剂；脂磷壁酸，一种Toll样受体2/6激动剂；尼日利亚菌素，一种含pyrin结构域的NOD样受体家族3激活剂）以及奥沙利铂和紫杉醇化疗诱导的周围神经病变所诱导的痛觉过敏，仅在雄性大鼠中有所减轻。在去势或鞘内注射G蛋白偶联雌激素受体30（GPER）mRNA反义寡核苷酸后，HMWH在雌性大鼠中产生抗痛觉过敏作用。在用奥沙利铂处理过的大鼠培养的伤害感受器中，HMWH可逆转雄性和经GPER反义处理的雌性大鼠伤害感受器的敏化，但不能逆转性腺完整的雌性大鼠的伤害感受器敏化。对于前列腺素E2（PGE2）诱导的致敏伤害感受器痛觉过敏的延长，也观察到了HMWH诱导的抗痛觉过敏中G蛋白偶联雌激素受体依赖性的性别差异。在致敏大鼠中，HMWH在PGE2注射后30分钟抑制早期的、蛋白激酶A依赖性的痛觉过敏，在雌雄大鼠中均如此；在PGE2注射后4小时测量，HMWH仅在雄性大鼠和经GPER反义处理的雌性大鼠中抑制PGE2痛觉过敏的蛋白激酶Cε（PKCε）依赖性延长。在雌性大鼠中，HMWH抑制了PKCε激动剂ψεRACK在对照但非致敏伤害感受器中诱导的痛觉过敏。两种GPER第二信使细胞外调节激酶1/2和非受体酪氨酸激酶的抑制剂，也在奥沙利铂化疗诱导的周围神经病变的雌性大鼠中揭示了HMWH的抗痛觉过敏作用，在这种情况下，伤害感受器既被致敏又被激活。我们的结果支持在由模式识别受体激动剂诱导的疼痛、慢性炎症性疼痛和神经性疼痛中，HMWH诱导的抗痛觉过敏存在G蛋白偶联雌激素受体依赖性的性别差异，其由致敏伤害感受器中PKCε下游信号变化介导。
