Sudo Roberto T, Hayashida Kenichiro, Santos Aluizio N, Kawatani Masahito, Monteiro Carlos Es, Moreira Roberto D, Trachez Margarete M, Montes Guilherme C, Zapata-Sudo Gisele
Program of Research in Drug Development of Biomedical Science, Institute of Federal University of Rio de Janeiro, Rio de Janeiro, Brazil,
Post-Graduation Program in Medicine (General Surgery) of Federal University of Rio de Janeiro, Rio de Janeiro, Brazil,
J Pain Res. 2018 Oct 30;11:2453-2462. doi: 10.2147/JPR.S169637. eCollection 2018.
To demonstrate the antinociceptive and antihypersensitivity mechanisms of Cris-104 (1-{2-[5-(4-fluorophenyl)-1H-pyrazol-4-yl]ethyl}piperidine), a novel selective αβ* nicotinic acetylcholine receptor (nAChR) agonist, in rodent acute/inflammatory and chronic pain models.
Hot-plate and formalin tests in mice were used to examine Cris-104-induced antinociceptive effects on thermal/inflammatory pain. Cris-104 effects on hypersensitivity, norepinephrine (NE) release in the spinal dorsal horn, and neuronal activity in the locus coeruleus (LC) were examined in rats with lumbar spinal nerve ligation using behavioral, microdialysis, and extracellular recording methods. Cris-104 effects on spontaneous locomotion were examined in an open-field test.
Cris-104 induced dose-dependent antinociception effects in hot-plate and formalin tests, and these effects were blocked by the general nAChR antagonist mecamylamine, the selective αβ* nAChR antagonist dihydro-beta-erythroidine, and the α-adrenoceptor antagonist yohimbine, but not by the α-adrenoceptor antagonist prazosin. Systemic and spinally perfused Cris-104 increased NE concentrations in microdialysates from the spinal cord in both normal and SNL rats. Systemic Cris-104 increased neuronal activity in the LC of normal rats. Mecamylamine blocked the effects of Cris-104 on spinal NE release and LC neuronal activity. Systemic Cris-104 did not affect locomotor activity significantly.
The αβ neuronal nAChR agonist, Cris-104, was effective for treatment of pain via descending noradrenergic inhibition of pain signaling.
在啮齿动物急性/炎症性和慢性疼痛模型中，证明新型选择性αβ*烟碱型乙酰胆碱受体（nAChR）激动剂Cris-104（1-{2-[5-(4-氟苯基)-1H-吡唑-4-基]乙基}哌啶）的抗伤害感受和抗超敏反应机制。
采用小鼠热板法和福尔马林试验，研究Cris-104对热/炎症性疼痛的抗伤害感受作用。采用行为学、微透析和细胞外记录方法，在腰段脊神经结扎大鼠中，研究Cris-104对超敏反应、脊髓背角去甲肾上腺素（NE）释放以及蓝斑（LC）神经元活动的影响。在旷场试验中研究Cris-104对自发运动的影响。
在热板法和福尔马林试验中，Cris-104诱导剂量依赖性抗伤害感受作用，这些作用被非选择性nAChR拮抗剂美加明、选择性αβ* nAChR拮抗剂二氢β-刺桐碱和α-肾上腺素能受体拮抗剂育亨宾阻断，但不被α-肾上腺素能受体拮抗剂哌唑嗪阻断。全身和脊髓灌注Cris-104均可增加正常和脊髓神经结扎（SNL）大鼠脊髓微透析液中的NE浓度。全身给予Cris-104可增加正常大鼠LC中的神经元活动。美加明阻断了Cris-104对脊髓NE释放和LC神经元活动的影响。全身给予Cris-104对运动活动无明显影响。
αβ神经元nAChR激动剂Cris-104通过下行去甲肾上腺素能抑制疼痛信号传导有效治疗疼痛。
