Schröder Wolfgang, Alique Matilde, Herrero Juan Fernando
Grünenthal Innovation, Translational Science and Strategy, Pharmacology and Biomarker Development, Grünenthal GmbH, Zieglerstrasse 6, 52078 Aachen, Germany.
Dept. Biology Systems, Unit of Physiology, Faculty of Medicine, Universidad de Alcala, Campus Universitario, 28871 Alcala de Henares, Spain.
Eur J Pharmacol. 2016 Jan 5;770:147-53. doi: 10.1016/j.ejphar.2015.11.042. Epub 2015 Nov 23.
MrgC receptors are selectively expressed on peripheral and central terminals of small calibre nociceptive fibres. Peptide agonists of the MrgC receptor were reported to modulate nociceptive transmission exerting either pro- or antinociceptive effects depending on site of action and pain model used. Here, we investigated the effect of intraplantar and intrathecal administration of the selective MrgC receptor agonist BAM6-22 on mechanically and electrically evoked nociceptive reflex activity as a uniform readout measure in naïve, monoarthritic and mononeuropathic rats. In naïve rats, intraplantar BAM6-22 enhanced, whereas intrathecal BAM6-22 did not modulate mechanically-evoked nociceptive reflex activity. In monoarthritic rats, intraplantar BAM6-22 had no effect, whereas intrathecal BAM6-22 inhibited mechanically evoked nociceptive reflex activity. In mononeuropathic rats, BAM6-22 reduced mechanically evoked nociceptive reflex activity after both intraplantar and intrathecal administration. BAM6-22 did not modulate electrically evoked nociceptive reflex activity in any condition. Thus, the results of the present investigation confirm and add to previous studies demonstrating that site of action, (patho)-physiological state and stimulus modality determine the effect quality of MrgC receptor agonists. It still needs to be explored how concurrent activation of peripheral and spinal MrgC receptors modulates nociceptive processing under conditions of both acute and chronic pain to evaluate the therapeutic potential of putative small molecule MrgC receptor agonists as innovative analgesics.
MrgC受体选择性地表达于小口径伤害性纤维的外周和中枢终末。据报道，MrgC受体的肽类激动剂可调节伤害性传递，根据作用部位和所使用的疼痛模型，可产生促伤害性或抗伤害性作用。在此，我们研究了在未处理的、单关节炎和单神经病变大鼠中，足底内和鞘内注射选择性MrgC受体激动剂BAM6-22对机械性和电诱发的伤害性反射活动的影响，将其作为一种统一的读数测量方法。在未处理的大鼠中，足底内注射BAM6-22增强了机械性诱发的伤害性反射活动，而鞘内注射BAM6-22则未对其产生调节作用。在单关节炎大鼠中，足底内注射BAM6-22没有效果，而鞘内注射BAM6-22抑制了机械性诱发的伤害性反射活动。在单神经病变大鼠中，足底内和鞘内注射BAM6-22后均降低了机械性诱发的伤害性反射活动。在任何情况下，BAM6-22均未调节电诱发的伤害性反射活动。因此，本研究结果证实并补充了先前的研究，表明作用部位、（病理）生理状态和刺激方式决定了MrgC受体激动剂的效应性质。在急性和慢性疼痛条件下，外周和脊髓MrgC受体的同时激活如何调节伤害性处理，以评估推定的小分子MrgC受体激动剂作为创新镇痛药的治疗潜力，仍有待探索。
