Spinal Activation of Tropomyosin Receptor Kinase-B Recovers the Impaired Endogenous Analgesia in Neuropathic Pain Rats
Spinal Activation of Tropomyosin Receptor Kinase-B Recovers the Impaired Endogenous Analgesia in Neuropathic Pain Rats
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DOI：
10.1213/ane.0000000000003592
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发表时间：
2019-08-01
影响因子：
5.7
通讯作者：
Saito, Shigeru
中科院分区：
文献类型：
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作者：
Kato, Daiki;Suto, Takashi;Saito, Shigeru
背景：虽然内源性镇痛在控制疼痛状态中起重要作用，但与健康个体相比，慢性疼痛患者表现出较低的内源性镇痛。在大鼠中，作为内源性镇痛指标的有害刺激诱导镇痛（NSIA）在脊髓神经结扎（SNL6W）后6周减弱。最近一项对去甲肾上腺素能纤维缺失的大鼠的研究表明，去甲肾上腺素能纤维对NSIA至关重要。也有报道称脑源性神经营养因子增加脊髓去甲肾上腺素能纤维。因此，本研究考察了脑源性神经营养因子受体TrkB激活对SNL6W大鼠NSIA受损的影响。此外，我们还研究了内源性镇痛对急性切口痛的影响。方法：每天5次腹腔注射7,8-二羟黄酮（7,8- dhf， TrkB激动剂，5 mg/kg），在前爪注射辣椒素（250 μ g） 30分钟后，通过测量左（神经结扎对侧）后爪的戒断阈值增量来检测NSIA。K252a （TrkB拮抗剂，2 μ g）鞘内给药5天。在注射辣椒素之前，在鞘内给药伊唑赞（α - 2肾上腺素受体拮抗剂，30 μ g）、阿托品（毒蕈碱拮抗剂，30 μ g）和普萘洛尔（非选择性β -肾上腺素受体拮抗剂，30 μ g） 15分钟。采用微透析和免疫组化检测脊髓背角去甲肾上腺素能的可塑性。在左后爪（神经结扎的对侧）行后爪切口。数据分析采用单因素方差分析或双因素重复测量单因素方差分析，然后采用Bonferroni校正的Student t检验。结果：每天5次腹腔注射7,8- dhf可恢复SNL6W大鼠的减毒NSIA (n = 7, P = 0.002；估计治疗效果[95% CI]: 62.9 [27.0-98.7] g)，这种作用可被每天5次鞘内联合注射K252a阻断（n = 6, P < 0.001; -57.8[-78.3至-37.2]g）。单次鞘内给药咪唑嗪（n = 8, P < 0.001; -61.6[-92.4至-30.9]g）和阿托品（n = 8, P = 0.003; -52.6[-73.3至-31.9]g）也能抑制这种作用，但心得安不能。此外，7,8- dhf增加了SNL6W大鼠脊髓背角的去甲肾上腺素能纤维和前爪辣椒素注射后的去甲肾上腺素释放。此外，反复注射7,8- dhf可防止SNL6W大鼠切口疼痛延迟恢复。结论：脊髓活化TrkB可能通过改善肾上腺素能可塑性来恢复减弱的内源性镇痛，从而预防术后疼痛延长。
BACKGROUND: Although endogenous analgesia plays an important role in controlling pain states, chronic pain patients exhibit decreased endogenous analgesia compared to healthy individuals. In rats, noxious stimulus-induced analgesia (NSIA), which is an indicator of endogenous analgesia, diminished 6 weeks after spinal nerve ligation (SNL6W). A recent study in rats with deleted noradrenergic fibers demonstrated that the noradrenergic fibers were essential to NSIA. It has also been reported that brain-derived neurotrophic factor increased spinal noradrenergic fibers. Therefore, this study examined the effect of TrkB activation, which is the receptor for brain-derived neurotrophic factor, on impaired NSIA in SNL6W rats. In addition, we also examined the effect of endogenous analgesia on acute incisional pain. METHODS: After 5 daily intraperitoneal injections of 7,8-dihydroxyflavone (7,8-DHF, TrkB agonist, 5 mg/kg), NSIA was examined by measuring the withdrawal threshold increment in the left (contralateral to nerve ligation) hindpaw at 30 minutes after capsaicin injection (250 mu g) in the forepaw. K252a (TrkB antagonist, 2 mu g) was administrated intrathecally for 5 days. Idazoxan (alpha 2 adrenoceptor antagonist, 30 mu g), atropine (muscarinic antagonist, 30 mu g), and propranolol (nonselective beta adrenoceptor antagonist, 30 mu g) were administered intrathecally for 15 minutes before capsaicin injection. Microdialysis and immunohistochemistry were performed to examine the noradrenergic plasticity in the spinal dorsal horn. A hindpaw incision was performed on the left (contralateral to nerve ligation) hindpaw. Data were analyzed by 1-way analyses of variance or 2-way repeated-measures 1-way analysis of variance followed by a Student t test with Bonferroni correction. RESULTS: Five daily intraperitoneal injections of 7,8-DHF restored the attenuated NSIA in SNL6W rats (n = 7, P = .002; estimated treatment effect [95% CI]: 62.9 [27.0-98.7] g), with this effect blocked by 5 daily intrathecal coadministrations of K252a (n = 6, P < .001; -57.8 [-78.3 to -37.2] g). This effect was also inhibited by a single intrathecal administration of idazoxan (n = 8, P < .001; -61.6 [-92.4 to -30.9] g) and atropine (n = 8, P = .003; -52.6 [-73.3 to -31.9] g), but not by propranolol. Furthermore, 7,8-DHF increased the noradrenergic fiber in the spinal dorsal horn and the noradrenaline release in response to the capsaicin injection in the forepaw in SNL6W rats. In addition, repeated injections of 7,8-DHF prevented delayed recovery from incisional pain in SNL6W rats. CONCLUSIONS: Spinal activation of TrkB may recover the attenuated endogenous analgesia by improving the adrenergic plasticity, thereby leading to prevention of pain prolongation after surgery.