Department of Pharmaceutical Biosciences, Uppsala University, P.O. Box 591, S-751 24, Uppsala, Sweden.
Department of Genetics, and Center of Alcohol & Substance Use Studies, Rutgers University, Piscataway, NJ, 08854-8001, USA.
Eur J Pharmacol. 2021 Feb 5;892:173820. doi: 10.1016/j.ejphar.2020.173820. Epub 2020 Dec 17.
Of painful conditions, somatic pain of acute nociceptive origin can be effectively managed clinically, while neuropathic pain of chronic neuropathy origin is difficult to control. For molecules involved in pain sensation, substance P (SP) is algesic, exacerbating painful sensation, while its amino-terminal fragment, heptapeptide SP, confers biological activities different from its full-length parent neuropeptide precursor. We previously demonstrated SP interaction with pain processing to alleviate chronic pain. Here we evaluated SP and its C-terminal amidated analogue SPamide, together with SP and opioid agonist DAMGO. We tested mouse behaviors of both acute somatic pain in tail-flick latency assay, and neuropathic pain in sciatic nerve injury model of chronic constriction injury (CCI). DAMGO produced dose-dependent analgesia for somatic pain as expected, so did both SP and its analogue SPamide, while SP yielded the opposite effect of algesia, in a phenomenon we termed 'contrintus', meaning 'opposite from within' to denote that two peptides of the same origin (SP and its metabolic fragment SP) produced opposite effects. In CCI model, DAMGO showed a general reduction in allodynia sensitivity for both nerve-injured and normal paws, without selective effect for neuropathic pain, consistent with clinical observation that opioids are less effective for chronic neuropathic pain. On the other hand, both SP and SPamide displayed dose-dependent anti-allodynia effect that is selective for neuropathic pain. These findings suggest that SP and its analogue may be useful for developing pharmaceuticals to treat neuropathic pain.
在疼痛病症中，急性伤害感受源的躯体疼痛可以通过临床手段有效地进行控制，而慢性神经病变源的神经性疼痛则难以控制。对于涉及疼痛感知的分子，P 物质（SP）具有痛觉过敏作用，会加剧疼痛感觉，而其氨基末端片段，七肽 P 物质，则赋予与其全长母神经肽前体不同的生物学活性。我们之前已经证明 SP 与疼痛处理相互作用以减轻慢性疼痛。在这里，我们评估了 SP 及其 C 端酰胺化类似物 SPamide，以及 SP 和阿片类激动剂 DAMGO。我们测试了 SP 和阿片类激动剂 DAMGO 对尾部闪烁潜伏期测定法中的急性躯体疼痛和坐骨神经损伤慢性压迫性损伤（CCI）模型中的神经性疼痛的小鼠行为的影响。DAMGO 对躯体疼痛产生了剂量依赖性的镇痛作用，这与 SP 和其类似物 SPamide 相同，而 SP 则产生了痛觉过敏的相反作用，我们将这种现象称为“contrintus”，意思是“来自内部的相反”，表示来自同一来源（SP 和其代谢片段 SP）的两种肽产生相反的作用。在 CCI 模型中，DAMGO 对神经损伤和正常爪子的所有痛觉过敏敏感性都表现出普遍降低，但对神经性疼痛没有选择性作用，这与临床观察一致，即阿片类药物对慢性神经性疼痛的效果较差。另一方面，SP 和 SPamide 均表现出剂量依赖性的抗所有痛觉过敏作用，对神经性疼痛具有选择性。这些发现表明，SP 和其类似物可能有助于开发用于治疗神经性疼痛的药物。
