The role of carbon monoxide on the anti-nociceptive effects and expression of cannabinoid 2 receptors during painful diabetic neuropathy in mice
The role of carbon monoxide on the anti-nociceptive effects and expression of cannabinoid 2 receptors during painful diabetic neuropathy in mice
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DOI：
10.1007/s00213-016-4271-4
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发表时间：
2016-06-01
影响因子：
3.4
通讯作者：
Pol, Olga
中科院分区：
文献类型：
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作者：
Castany, Silvia;Carcole, Mireia;Pol, Olga
大麻素2受体（CB2R）的激活可以减轻慢性疼痛，但由诱导血红素加氧酶1 （HO-1）合成的一氧化碳在选择性CB2R激动剂JWH-015在疼痛性糖尿病神经病变中产生的抗伤害性作用中的作用尚不清楚。在链脲佐菌素（STZ）诱导的糖尿病小鼠中，研究了单独皮下给药或联合腹腔给药10 mg/kg的一氧化碳释放分子（三羰基二氯（II）二聚体（CORM-2））或HO-1诱导剂化合物（钴原卟啉IX (CoPP)）的抗异动和抗痛觉作用。还评估了HO-1抑制剂（锡原卟啉IX (SnPP)）和CB2R拮抗剂（AM630）对JWH-015抗伤害性作用的逆转。此外，我们还评估了CORM-2和CoPP单独或联合jwho -015治疗糖尿病小鼠HO-1、神经元一氧化氮合酶（NOS1）和CB2R的蛋白水平。JWH-015剂量依赖性抑制糖尿病引起的超敏反应。JWH-015与CORM-2或CoPP合用可增强其作用，而与SnPP或AM630合用可逆转其作用。在jwh -015处理小鼠中，CORM-2和CoPP处理诱导的HO-1蛋白水平升高进一步增强。所有治疗均同样增强了CB2R的外周表达，避免了糖尿病诱导的脊髓NOS1过表达。HO-1的激活增强了JWH-015对糖尿病小鼠的抗伤害性作用，提示JWH-015与CORM-2或CoPP共同给药可能是治疗小鼠疼痛性糖尿病神经病变的一种有趣的方法。
The activation of cannabinoid 2 receptors (CB2R) attenuates chronic pain, but the role played by carbon monoxide synthesized by the inducible heme oxygenase 1 (HO-1) on the anti-nociceptive effects produced by a selective CB2R agonist, JWH-015, during painful diabetic neuropathy remains unknown.In streptozotocin (STZ)-induced diabetic mice, the anti-allodynic and anti-hyperalgesic effects of the subcutaneous administration of JWH-015 alone or combined with the intraperitoneal administration of a carbon monoxide-releasing molecule (tricarbonyldichlororuthenium(II) dimer (CORM-2)) or an HO-1 inducer compound (cobalt protoporphyrin IX (CoPP)) at 10 mg/kg were evaluated. Reversion of JWH-015 anti-nociceptive effects by the administration of an HO-1 inhibitor (tin protoporphyrin IX (SnPP)) and a CB2R antagonist (AM630) was also evaluated. Furthermore, the protein levels of HO-1, neuronal nitric oxide synthase (NOS1), and CB2R in diabetic mice treated with CORM-2 and CoPP alone or combined with JWH-015 were also assessed.The administration of JWH-015 dose dependently inhibited hypersensitivity induced by diabetes. The effects of JWH-015 were enhanced by their coadministration with CORM-2 or CoPP and reversed by SnPP or AM630. The increased protein levels of HO-1 induced by CORM-2 and CoPP treatments were further enhanced in JWH-015-treated mice. All treatments similarly enhanced the peripheral expression of CB2R and avoided the spinal cord over-expression of NOS1 induced by diabetes.The activation of HO-1 enhanced the anti-nociceptive effects of JWH-015 in diabetic mice, suggesting that coadministration of JWH-015 with CORM-2 or CoPP might be an interesting approach for the treatment of painful diabetic neuropathy in mice.