Zhang Pinyi, Bu Jianlong, Wu Xiaohong, Deng Lin, Chi Meng, Ma Chao, Shi Xiaoding, Wang Guonian
Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China.
Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China.
J Pain Res. 2020 Oct 15;13:2617-2627. doi: 10.2147/JPR.S274225. eCollection 2020.
Sustained morphine treatment for cancer pain has been limited due to analgesic tolerance. Opioid receptor internalization and desensitization mediated by downregulation of mu-opioid receptor (MOR) expression have been confirmed as one of the mechanisms of chronic morphine tolerance. In addition to the opiate system, the α2-adrenergic system is involved in the development of morphine tolerance. Several studies reported that co-administration of α2-adrenoceptor agonist dexmedetomidine inhibits morphine tolerance in normal or neuropathic pain animals. However, the effect of dexmedetomidine on morphine tolerance has not been studied in cancer pain. Therefore, we investigated the effect of intrathecal injection of dexmedetomidine on the development of morphine tolerance in cancer pain and on the expression of MOR in the spinal cord of morphine-tolerant cancer pain rats.
The model was established using a rat's right hind paw injection of Walker 256 cancer cells. Subcutaneous morphine (10mg/kg) was administrated twice daily for 7 days; meanwhile, the rats received intrathecal α2-adrenoceptor agonist dexmedetomidine (10μ/kg) or antagonist MK-467 (0.25mg/kg) in test groups. Rats receiving drug vehicle served as the control group. Antinociception was detected by von Frey filaments and hot-plate tests. The expression of MOR in the spinal cord was examined through real-time reverse transcription polymerase chain reaction and Western blotting. The data were analyzed via analysis of variance followed by Student -test with Bonferroni correction.
Seven-day chronic morphine administration elicited notable analgesic tolerance in the rats with cancer pain. Co-administration of α2-adrenoceptor agonist dexmedetomidine enhanced morphine analgesia and attenuated morphine tolerance, which could be blocked by α2-adrenoceptor antagonist MK-467. Furthermore, pre-treatment of dexmedetomidine significantly upregulated MOR protein expression without a notable change in MOR mRNA expression in the spinal cord.
Our findings suggest that intrathecal injection of dexmedetomidine enhanced morphine analgesia and attenuated morphine tolerance in cancer pain, potentially by upregulating MOR expression in the spinal cord. The α2-adrenoceptor agonist may provide a more versatile analgesia option for morphine treatment for cancer pain.
由于镇痛耐受性，吗啡持续治疗癌痛受到限制。由μ-阿片受体（MOR）表达下调介导的阿片受体内化和脱敏已被确认为慢性吗啡耐受性的机制之一。除阿片系统外，α2-肾上腺素能系统也参与吗啡耐受性的形成。多项研究报道，联合使用α2-肾上腺素能受体激动剂右美托咪定可抑制正常或神经性疼痛动物的吗啡耐受性。然而，右美托咪定对癌痛吗啡耐受性的影响尚未见研究报道。因此，我们研究了鞘内注射右美托咪定对癌痛吗啡耐受性形成及吗啡耐受癌痛大鼠脊髓中MOR表达的影响。
采用大鼠右后足注射Walker 256癌细胞建立模型。皮下注射吗啡（10mg/kg），每日2次，共7天；同时，试验组大鼠鞘内注射α2-肾上腺素能受体激动剂右美托咪定（10μg/kg）或拮抗剂MK-467（0.25mg/kg）。接受药物载体的大鼠作为对照组。通过von Frey细丝和热板试验检测镇痛效果。通过实时逆转录聚合酶链反应和蛋白质免疫印迹法检测脊髓中MOR的表达。数据采用方差分析，随后进行Bonferroni校正的Student检验进行分析。
连续7天给予慢性吗啡可使癌痛大鼠产生明显的镇痛耐受性。联合使用α2-肾上腺素能受体激动剂右美托咪定可增强吗啡镇痛作用并减弱吗啡耐受性，而α2-肾上腺素能受体拮抗剂MK-467可阻断这一作用。此外，右美托咪定预处理可显著上调脊髓中MOR蛋白表达，而MOR mRNA表达无明显变化。
我们的研究结果表明，鞘内注射右美托咪定可增强癌痛中的吗啡镇痛作用并减弱吗啡耐受性，可能是通过上调脊髓中MOR的表达实现的。α2-肾上腺素能受体激动剂可能为癌痛吗啡治疗提供更通用的镇痛选择。
