da Silva Juliana Figueira, Castro-Junior Célio José, Oliveira Sara Marchesan, Dalmolin Gerusa Duarte, Silva Cássia Regina, Vieira Luciene Bruno, Diniz Danuza Montijo, Cordeiro Marta do Nascimento, Ferreira Juliano, Souza Alessandra Hubner, Gomez Marcus Vinícius
Department of Neurotransmitters, Institute of Education and Research, Santa Casa, Belo Horizonte, Minas Gerais, 30150-240, Brazil.
Department of Neurotransmitters, Institute of Education and Research, Santa Casa, Belo Horizonte, Minas Gerais, 30150-240, Brazil.
Toxicon. 2015 Dec 15;108:53-61. doi: 10.1016/j.toxicon.2015.09.043. Epub 2015 Oct 3.
Venom-derived peptides constitute a unique source of drug prototypes for the pain management. Many of them can modulate voltage-gated calcium channels that are central in the processing of pain sensation. PhTx3-4 is a peptide isolated from Phoneutria nigriventer venom, which blocks high voltage-activated calcium channels with low specificity, thereby leading to neuroprotection in models of ischemia in vitro. The aim of the present work was evaluating the potential of intrathecal PhTx3-4 in the reversal of different nociceptive states in mice, furthermore assessing the potential of PhTx3-4 in triggering motor side effects. We found that bellow 100 pmol/site, PhTx3-4 did not cause major motor side effects. By comparison, ω-conotoxin MVIIA and ω-conotoxin MVIIC triggered motor side effects at the doses of 10 and 100 pmol/site, respectively. Also, PhTx3-4 (30 pmol/site) caused no significant alterations in the forced locomotor activity test (rotarod) and in the exploratory activity test (versamax). In a model of inflammatory persistent pain (formalin test), PhTx3-4 reversed nociceptive behavior both pre or post-administered, although this effect was observed only at the inflammatory phase of the test and not at the neurogenic phase. Comparatively, ω-conotoxin MVIIC was effective only when post-administered in the formalin test. Nonetheless, PhTx3-4 treatment was devoid of action in acute nociceptive thermal model (hotplate test), whereas morphine showed efficacy in this test. Efficacy of PhTx3-4 in the formalin test was associated with inhibition of formalin-induced glutamate release in the cerebrospinal fluid. PhTx3-4, but not ω-conotoxin MVIIC, reversed NMDA-induced nociceptive behavior indicating a putative role of PhTx3-4 at ionotropic glutamate receptors. Finally, we observed efficacy of PhTx3-4 in ameliorating mechanical hypersensitivity induced by paw incision, a post-operative and more clinically relevant pain model. Taken together, our data show that PhTx3-4 possesses antinociceptive effect in different models of pain in mice, suggesting that this toxin may serve as drug prototype for pain control.
毒液衍生肽是疼痛管理中药物原型的独特来源。其中许多肽可以调节电压门控钙通道，而这些通道在痛觉处理中起核心作用。PhTx3-4是一种从黑腹舞蛛毒液中分离出的肽，它以低特异性阻断高电压激活的钙通道，从而在体外缺血模型中产生神经保护作用。本研究的目的是评估鞘内注射PhTx3-4逆转小鼠不同伤害性状态的潜力，此外还评估PhTx3-4引发运动副作用的可能性。我们发现，在每部位低于100皮摩尔时，PhTx3-4不会引起主要的运动副作用。相比之下，ω-芋螺毒素MVIIA和ω-芋螺毒素MVIIC分别在每部位10和100皮摩尔的剂量下引发运动副作用。此外，PhTx3-4（每部位30皮摩尔）在强迫运动活动试验（转棒试验）和探索性活动试验（Versamax试验）中未引起显著变化。在炎症性持续性疼痛模型（福尔马林试验）中，PhTx3-4在给药前或给药后均可逆转伤害性行为，尽管这种效应仅在试验的炎症期观察到，而在神经源性期未观察到。相比之下，ω-芋螺毒素MVIIC仅在福尔马林试验中给药后才有效。然而，PhTx3-4治疗在急性伤害性热模型（热板试验）中无效，而吗啡在该试验中显示出疗效。PhTx3-4在福尔马林试验中的疗效与抑制福尔马林诱导的脑脊液中谷氨酸释放有关。PhTx3-4而非ω-芋螺毒素MVIIC可逆转NMDA诱导的伤害性行为，表明PhTx3-4在离子型谷氨酸受体上可能具有作用。最后，我们观察到PhTx3-4在改善 paw incision 诱导的机械性超敏反应方面具有疗效，paw incision 是一种术后且更具临床相关性的疼痛模型。综上所述，我们的数据表明PhTx3-4在小鼠不同疼痛模型中具有镇痛作用，提示这种毒素可能作为疼痛控制的药物原型。
