Ohta Jo, Suto Takashi, Kato Daiki, Hiroki Tadanao, Obata Hideaki, Saito Shigeru
Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma 371-8511, Japan.
Department of Anesthesiology and Center for Pain Management, Fukushima Medical University, 1 Hikariga-oka, Fukushima, Fukushima 960-1295, Japan.
Brain Res. 2020 Jan 15;1727:146568. doi: 10.1016/j.brainres.2019.146568. Epub 2019 Nov 27.
Preoperative pain and impaired endogenous analgesia are risk factors of chronic postsurgical persistent pain (CPSP). A Chronic neuropathic pain model induced by spinal nerve ligation (SNL6W) shows impaired endogenous analgesia and delayed recovery from incisional pain. Repeated amitriptyline treatment can restore the endogenous analgesia, but its effects on delayed recovery are not clear.
A plantar incision was made on the side contralateral to the nerve ligation in SNL6W rats. Withdrawal thresholds were measured by von Frey filament test until 28 d after surgery. Amitriptyline (10 mg·kg·d) or vehicle was administered for 13 d perioperatively. To examine the roles of noradrenergic and cholinergic signals in the spinal dorsal horn, pharmacological antagonism, measurement of each neurotransmitter concentration, and immunohistochemistry were conducted.
Recovery of the withdrawal threshold of SNL6W animals to pre-incision values required 28 d after surgery, while naive animals recovered within 14 d. Intrathecal injection of alpha2 adrenoceptor antagonist (idazoxan) or muscarinic cholinergic receptor antagonist (atropine) decreased the withdrawal threshold on POD14 and 21 in naive animals, but not in SNL6W rats. Repeated amitriptyline treatment attenuated the delayed recovery in SNL6W rats, and the effect was antagonized by muscarinic cholinergic receptor antagonist. Beside the concentration of acetylcholine and its synthetic enzyme were not altered by the treatment.
Noradrenergic and cholinergic analgesia, which is necessary for normal recovery, is lost in the SNL6W rats. A strategy to enhance endogenous analgesia using antidepressants, rather than simple analgesia, may help to prevent CPSP in chronic pain patients.
术前疼痛和内源性镇痛受损是慢性术后持续性疼痛（CPSP）的危险因素。由脊神经结扎（SNL6W）诱导的慢性神经性疼痛模型显示内源性镇痛受损以及切口痛恢复延迟。反复给予阿米替林治疗可恢复内源性镇痛，但对恢复延迟的影响尚不清楚。
在SNL6W大鼠神经结扎对侧进行足底切口。通过von Frey细丝试验测量撤药阈值，直至术后28天。围手术期给予阿米替林（10mg·kg·d）或赋形剂，持续13天。为了研究去甲肾上腺素能和胆碱能信号在脊髓背角中的作用，进行了药理学拮抗、每种神经递质浓度的测量以及免疫组织化学。
SNL6W动物的撤药阈值恢复到切口前值需要术后28天，而正常动物在14天内恢复。鞘内注射α2肾上腺素能受体拮抗剂（咪唑克生）或毒蕈碱胆碱能受体拮抗剂（阿托品）可降低正常动物术后第14天和21天的撤药阈值，但对SNL6W大鼠无效。反复给予阿米替林治疗可减轻SNL6W大鼠的恢复延迟，且该作用被毒蕈碱胆碱能受体拮抗剂拮抗。此外，治疗并未改变乙酰胆碱及其合成酶的浓度。
SNL6W大鼠丧失了正常恢复所必需的去甲肾上腺素能和胆碱能镇痛作用。使用抗抑郁药增强内源性镇痛而非单纯镇痛的策略可能有助于预防慢性疼痛患者的CPSP。
