Paton K F, Kumar N, Crowley R S, Harper J L, Prisinzano T E, Kivell B M
School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, New Zealand.
Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, USA.
Eur J Pain. 2017 Jul;21(6):1039-1050. doi: 10.1002/ejp.1002. Epub 2017 Feb 3.
Drugs activating the mu opioid receptor are routinely used to treat severe acute and chronic pain. Unfortunately, side effects including nausea, constipation, respiratory depression, addiction and tolerance can limit clinical utility. In contrast, kappa opioid receptor (KOPr) agonists, such as Salvinorin A (SalA), have analgesic properties with little potential for abuse.
We evaluated SalA and the novel analogue β-tetrahydropyran Salvinorin B (β-THP SalB) for the ability to modulate pain and inflammation in vivo. The hot water tail-withdrawal assay, intradermal formalin-induced inflammatory pain and paclitaxel-induced neuropathic pain models were used to evaluate analgesic properties in mice. Tissue infiltration of inflammatory cells was measured by histology and flow cytometry.
β-tetrahydropyran Salvinorin B produced a longer duration of action in the tail-withdrawal assay compared to the parent compound SalA, and, like SalA and U50,488, β-THP SalB is a full agonist at the KOPr. In the formalin-induced inflammatory pain model, β-THP SalB and SalA significantly reduced pain score, paw oedema and limited the infiltration of neutrophils into the inflamed tissue. β-THP SalB and SalA supressed both mechanical and cold allodynia in the paclitaxel-induced neuropathic pain model, in a dose-dependent manner.
Structural modification of SalA at the C-2 position alters its analgesic potency and efficacy in vivo. Substitution with a tetrahydropyran group at C-2 produced potent analgesic and anti-inflammatory effects, including a reduction in paclitaxel-induced neuropathic pain. This study highlights the potential for KOPr agonists as analgesics with anti-inflammatory action and little risk of abuse.
Salvinorin A and the novel analogue β-THP Salvinorin B show analgesic effects in the tail-withdrawal and formalin assays. They reduce oedema and decrease neutrophil infiltration into inflamed tissue, and suppress mechanical and cold allodynia in paclitaxel-induced neuropathic pain.
激活μ阿片受体的药物常用于治疗严重的急性和慢性疼痛。不幸的是，包括恶心、便秘、呼吸抑制、成瘾和耐受性在内的副作用会限制其临床应用。相比之下，κ阿片受体（KOPr）激动剂，如Salvinorin A（SalA），具有镇痛特性且几乎没有滥用潜力。
我们评估了SalA和新型类似物β-四氢吡喃Salvinorin B（β-THP SalB）在体内调节疼痛和炎症的能力。采用热水甩尾试验、皮内注射福尔马林诱导的炎性疼痛和紫杉醇诱导的神经性疼痛模型来评估小鼠的镇痛特性。通过组织学和流式细胞术测量炎性细胞的组织浸润情况。
与母体化合物SalA相比，β-四氢吡喃Salvinorin B在甩尾试验中产生的作用持续时间更长，并且与SalA和U50,488一样，β-THP SalB是KOPr的完全激动剂。在福尔马林诱导的炎性疼痛模型中，β-THP SalB和SalA显著降低疼痛评分、爪部水肿，并限制中性粒细胞向炎症组织的浸润。在紫杉醇诱导的神经性疼痛模型中，β-THP SalB和SalA以剂量依赖性方式抑制机械性和冷觉异常性疼痛。
SalA在C-2位的结构修饰改变了其体内镇痛效力和效果。在C-2位用四氢吡喃基团取代产生了强效的镇痛和抗炎作用，包括减轻紫杉醇诱导的神经性疼痛。本研究突出了KOPr激动剂作为具有抗炎作用且几乎无滥用风险的镇痛药的潜力。
Salvinorin A和新型类似物β-THP Salvinorin B在甩尾试验和福尔马林试验中显示出镇痛作用。它们减轻水肿，减少中性粒细胞向炎症组织的浸润，并抑制紫杉醇诱导的神经性疼痛中的机械性和冷觉异常性疼痛。
