Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
Department of Chemistry, University of Virginia, Charlottesville, VA, USA.
Pain. 2018 Jun;159(6):1155-1165. doi: 10.1097/j.pain.0000000000001199.
A great need exists for the identification of new effective analgesics to treat sustained pain. However, most preclinical nociceptive assays measure behavioral responses evoked by noxious stimuli (ie, pain-stimulated behavior), which presents a challenge to distinguish between motor impairing and antinociceptive effects of drugs. Here, we demonstrate that chronic constriction injury (CCI) of the sciatic nerve elicits common pain-stimulated responses (ie, mechanical allodynia and thermal hyperalgesia) as well as reduces marble burying/digging behaviors that occur during the early stages of the neuropathy and resolve within 1 week. Although drugs representing distinct classes of analgesics (ie, morphine, valdecoxib, and gabapentin) reversed both CCI-induced and CCI-depressed nociceptive measures, diazepam lacked antinociceptive effects in all assays and the kappa-opioid receptor agonist U69593 reversed pain-stimulated, but not pain-depressed behaviors. In addition, we tested drugs targeting distinct components of the endocannabinoid system, including agonists at cannabinoid receptors type 1 (CB1) and type 2 (CB2), as well as inhibitors of the endocannabinoid-regulating enzymes fatty acid amide hydrolase and monoacylglycerol lipase. Each of these drugs reversed all CCI-induced nociceptive measures, with the exception of the fatty acid amide hydrolase inhibitor that reversed pain-stimulated behaviors, only. These findings support the use of the mouse marble-burying assay as a model of pain-depressed behavior within the first week of sciatic nerve injury to examine candidate analgesics. These data also support existing preclinical research that cannabinoid receptor agonists and inhibitors of endocannabinoid-regulating enzymes merit consideration for the treatment of pain.
非常需要鉴定新的有效镇痛药来治疗持续性疼痛。然而，大多数临床前伤害感受检测都测量有害刺激引起的行为反应（即疼痛刺激行为），这给区分药物的运动障碍和抗伤害感受作用带来了挑战。在这里，我们证明坐骨神经慢性缩窄性损伤（CCI）引起共同的疼痛刺激反应（即机械性痛觉过敏和热痛觉过敏），并减少在神经病早期发生的且在 1 周内消退的埋珠/挖掘行为。虽然代表不同类别的镇痛药（即吗啡、伐地昔布和加巴喷丁）的药物逆转了 CCI 诱导的和 CCI 抑制的伤害感受措施，但地西泮在所有检测中均缺乏抗伤害感受作用，而κ阿片受体激动剂 U69593 逆转了疼痛刺激的行为，但没有逆转疼痛抑制的行为。此外，我们测试了针对内源性大麻素系统不同成分的药物，包括大麻素受体 1（CB1）和 2（CB2）的激动剂，以及内源性大麻素调节酶脂肪酸酰胺水解酶和单酰基甘油脂肪酶的抑制剂。这些药物中的每一种都逆转了所有 CCI 诱导的伤害感受措施，但脂肪酸酰胺水解酶抑制剂除外，它仅逆转了疼痛刺激的行为。这些发现支持使用小鼠埋珠试验作为坐骨神经损伤后第一周内疼痛抑制行为的模型，以检查候选镇痛药。这些数据还支持现有的临床前研究，即大麻素受体激动剂和内源性大麻素调节酶抑制剂值得考虑用于治疗疼痛。
