Department of Pharmacology, Faculty of Medicine, University of Granada, 18071 Granada, Spain; Institute of Neuroscience, Biomedical Research Center, University of Granada, Parque Tecnológico de Ciencias de la Salud, 18100 Armilla, Granada, Spain.
Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain; Institute of Biopathology and Regenerative Medicine (IBIMER), Biomedical Research Center, University of Granada, Parque Tecnológico de Ciencias de la Salud, 18100 Armilla, Granada, Spain.
Neuropharmacology. 2018 Jun;135:328-342. doi: 10.1016/j.neuropharm.2018.03.025. Epub 2018 Mar 24.
Morphine induces peripherally μ-opioid-mediated antinociception to heat but not to mechanical stimulation. Peripheral sigma-1 receptors tonically inhibit μ-opioid antinociception to mechanical stimuli, but it is unknown whether they modulate μ-opioid heat antinociception. We hypothesized that sigma-1 receptors might play a role in the modality-specific peripheral antinociceptive effects of morphine and other clinically relevant μ-opioid agonists. Mechanical nociception was assessed in mice with the paw pressure test (450 g), and heat nociception with the unilateral hot plate (55 °C) test. Local peripheral (intraplantar) administration of morphine, buprenorphine or oxycodone did not induce antinociception to mechanical stimulation but had dose-dependent antinociceptive effects on heat stimuli. Local sigma-1 antagonism unmasked peripheral antinociception by μ-opioid agonists to mechanical stimuli, but did not modify their effects on heat stimulation. TRPV1+ and IB4+ cells are segregated populations of small neurons in the dorsal root ganglia (DRG) and the density of sigma-1 receptors was higher in IB4+ cells than in the rest of small nociceptive neurons. The in vivo ablation of TRPV1-expressing neurons with resiniferatoxin did not alter IB4+ neurons in the DRG, mechanical nociception, or the effects of sigma-1 antagonism on local morphine antinociception in this type of stimulus. However, it impaired the responses to heat stimuli and the effect of local morphine on heat nociception. In conclusion, peripheral opioid antinociception to mechanical stimuli is limited by sigma-1 tonic inhibitory actions, whereas peripheral opioid antinociception to heat stimuli (produced in TRPV1-expressing neurons) is not. Therefore, sigma-1 receptors contribute to the modality-specific peripheral effects of opioid analgesics.
吗啡诱导外周 μ 阿片受体介导的热痛觉，但不介导机械性刺激的痛觉。外周σ1 受体持续抑制 μ 阿片类药物对机械刺激的镇痛作用，但尚不清楚它们是否调节 μ 阿片类药物的热镇痛作用。我们假设 σ1 受体可能在吗啡和其他临床相关 μ 阿片类激动剂的特定模式外周镇痛作用中发挥作用。使用足底压力测试（450 g）评估机械性疼痛，使用单侧热板（55°C）测试评估热痛觉。局部外周（足底内）给予吗啡、丁丙诺啡或羟考酮不会引起机械刺激的镇痛作用，但对热刺激有剂量依赖性的镇痛作用。局部 σ1 拮抗剂使 μ 阿片类激动剂对机械刺激的外周镇痛作用显现出来，但不改变它们对热刺激的作用。TRPV1+和 IB4+细胞是背根神经节（DRG）中小神经元的分离群体，σ1 受体的密度在 IB4+细胞中高于其他小感觉神经元。用树脂毒素对 TRPV1 表达神经元进行体内消融，不会改变 DRG 中的 IB4+神经元、机械性疼痛觉或 σ1 拮抗剂对这种刺激下局部吗啡镇痛作用的影响。然而，它损害了对热刺激的反应以及局部吗啡对热痛觉的影响。总之，外周阿片类药物对机械刺激的镇痛作用受到 σ1 持续抑制性作用的限制，而外周阿片类药物对热刺激的镇痛作用（在 TRPV1 表达神经元中产生）不受限制。因此，σ1 受体有助于阿片类镇痛药的特定模式外周作用。
