Background: The delta opioid receptor (DOR) contributes to pain control, and a major challenge is the identification of DOR populations that control pain, analgesia, and tolerance. Astrocytes are known as important cells in the pathophysiology of chronic pain, and many studies report an increased prevalence of pain in women. However, the implication of astrocytic DOR in neuropathic pain and analgesia, as well as the influence of sex in this receptor activity, remains unknown.

Experimental Approach: We developed a novel conditional knockout (cKO) mouse line wherein DOR is deleted in astrocytes (named GFAP-DOR-KO), and investigated neuropathic mechanical allodynia as well as analgesia and analgesic tolerance in mutant male and female mice. Neuropathic cold allodynia was also characterized in mice of both sexes lacking DOR either in astrocytes or constitutively.

Results: Neuropathic mechanical allodynia was similar in GFAP-DOR-KO and floxed DOR control mice, and the DOR agonist SNC80 produced analgesia in mutant mice of both sexes. Interestingly, analgesic tolerance developed in cKO males and was abolished in cKO females. Cold neuropathic allodynia was reduced in mice with decreased DOR in astrocytes. By contrast, cold allodynia was exacerbated in full DOR KO females.

Conclusions: These findings show that astrocytic DOR has a prominent role in promoting cold allodynia and analgesic tolerance in females, while overall DOR activity was protective. Altogether this suggests that endogenous- and exogenous-mediated DOR activity in astrocytes worsens neuropathic allodynia while DOR activity in other cells attenuates this form of pain. In conclusion, our results show a sex-specific implication of astrocytic DOR in neuropathic pain and analgesic tolerance. These findings open new avenues for developing tailored DOR-mediated analgesic strategies.

背景：δ阿片受体 (DOR) 有助于疼痛控制，主要挑战是识别控制疼痛、镇痛和耐受的 DOR 群体。星形胶质细胞被认为是慢性疼痛病理生理学中的重要细胞，许多研究报告女性疼痛患病率增加。然而，星形细胞 DOR 在神经性疼痛和镇痛中的意义，以及性别对该受体活性的影响，仍然未知。

实验方法：我们开发了一种新型条件敲除 (cKO) 小鼠系，其中星形胶质细胞中的 DOR 被删除（称为 GFAP-DOR-KO），并研究了突变雄性和雌性小鼠的神经性机械异常性疼痛以及镇痛和镇痛耐受性。神经性冷异常性疼痛在星形胶质细胞或结构性缺乏 DOR 的雌雄小鼠中也有特征。

结果： GFAP-DOR-KO 和 floxed DOR 对照小鼠的神经性机械异常性疼痛相似，DOR 激动剂 SNC80 对两种性别的突变小鼠均产生镇痛作用。有趣的是，镇痛耐受性在 cKO 雄性中出现，而在 cKO 雌性中消失。星形胶质细胞 DOR 降低的小鼠的冷神经性异常性疼痛减轻。相比之下，完全 DOR KO 雌性中冷异常性疼痛加剧。

结论：这些研究结果表明，星形胶质细胞 DOR 在促进女性冷痛异常和镇痛耐受性方面具有显着作用，而总体 DOR 活性具有保护作用。总而言之，这表明星形胶质细胞中内源性和外源性介导的 DOR 活性会加重神经性异常性疼痛，而其他细胞中的 DOR 活性会减轻这种形式的疼痛。总之，我们的结果表明星形细胞 DOR 对神经性疼痛和镇痛耐受具有性别特异性。这些发现为开发定制的 DOR 介导的镇痛策略开辟了新途径。