Obara Ilona, Parkitna Jan Rodriguez, Korostynski Michal, Makuch Wioletta, Kaminska Dorota, Przewlocka Barbara, Przewlocki Ryszard
Department of Pain Pharmacology, Institute of Pharmacology PAS, Smetna 12, 31-343 Krakow, Poland Department of Molecular Neuropharmacology, Institute of Pharmacology PAS, Smetna 12, 31-343 Krakow, Poland.
Pain. 2009 Feb;141(3):283-291. doi: 10.1016/j.pain.2008.12.006. Epub 2009 Jan 14.
We investigated the efficacy of local intraplantar (i.pl.) injection of peptide and non-peptide mu-, delta- and kappa-opioid receptor agonists in rat models of inflammatory and neuropathic pain. Locally applied agonists dose-dependently reduced formalin-induced flinching of the inflamed paw and induced antiallodynic and antihyperalgesic effects in sciatic nerve ligation-induced neuropathic pain. These effects were mediated by peripheral opioid receptors localized at the side of tissue/nerve injury, as was demonstrated by selective and non-selective opioid receptors antagonists. The ED(50) dose range of mu- and kappa-agonists required to induce analgesia in neuropathy was much higher than the ED(50) for inflammation; moreover, only delta-agonists were effective in the same dose range in both pain models. Additionally, effective antinociception was achieved at a lower dose of peptide, compared to non-peptide, opioids. Such findings support the use of the peripheral administration of opioid peptides, especially delta-agonists, in treating chronic pain. Furthermore, in order to assess whether adaptations in the expression of opioid genes could underlie the clinical observation of reduced opioid effectiveness in neuropathic pain, we analyzed the abundance of opioid transcripts in the spinal cord and dorsal root ganglia (DRG) during the neuropathy and inflammation. Nerve injury down-regulated mRNA for all types of opioid receptors in the DRG, which is predicted to decrease in the synthesis of opioid receptors to possibly account for the reduced effectiveness of locally administered opioids in neuropathy. The obtained results differentiate inflammatory and neuropathic pain and provide a novel insight into the peripheral effectiveness of opioids in both types of pain.
我们研究了在炎症性疼痛和神经性疼痛大鼠模型中，足底局部（i.pl.）注射肽类和非肽类μ、δ和κ阿片受体激动剂的疗效。局部应用激动剂可剂量依赖性地减少福尔马林诱导的患侧爪部退缩，并在坐骨神经结扎诱导的神经性疼痛中产生抗痛觉过敏和抗痛觉超敏作用。选择性和非选择性阿片受体拮抗剂证明，这些作用是由位于组织/神经损伤部位的外周阿片受体介导的。在神经病变中诱导镇痛所需的μ和κ激动剂的ED(50)剂量范围远高于炎症时的ED(50)；此外，只有δ激动剂在两种疼痛模型的相同剂量范围内有效。此外，与非肽类阿片类药物相比，肽类阿片在较低剂量时就能产生有效的抗伤害感受作用。这些发现支持在治疗慢性疼痛时使用外周给予阿片肽，尤其是δ激动剂。此外，为了评估阿片类基因表达的适应性变化是否可能是神经性疼痛中阿片类药物有效性降低这一临床观察结果的基础，我们分析了神经病变和炎症过程中脊髓和背根神经节（DRG）中阿片类转录本的丰度。神经损伤下调了DRG中所有类型阿片受体的mRNA，预计这会减少阿片受体的合成，从而可能解释局部给予阿片类药物在神经病变中有效性降低的原因。所得结果区分了炎症性疼痛和神经性疼痛，并为阿片类药物在这两种疼痛类型中的外周有效性提供了新的见解。
