鞘内注射BRL52537（κ-阿片受体激动剂）、普瑞巴林（钙通道调节剂）、AF 353（P2X3受体拮抗剂）和A804598（P2X7受体拮抗剂）对神经性大鼠药物组合的等效线图分析

Isobolographic Analysis of Drug Combinations With Intrathecal BRL52537 (κ-Opioid Agonist), Pregabalin (Calcium Channel Modulator), AF 353 (P2X3 Receptor Antagonist), and A804598 (P2X7 Receptor Antagonist) in Neuropathic Rats.

作者信息

Jung Young-Hwan, Kim Yeo Ok, Han Jung Hyun, Kim Yong-Chul, Yoon Myung Ha

机构信息

From the *School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea; †Department of Anesthesiology and Pain Medicine, Chonnam National University, Medical School, Gwangju, Republic of Korea; ‡Department of Biomedical Science and Engineering at Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea; and §Center for Creative Biomedical Scientists at Chonnam National University, Gwangju, Republic of Korea.

出版信息

Anesth Analg. 2017 Aug;125(2):670-677. doi: 10.1213/ANE.0000000000001883.

DOI:10.1213/ANE.0000000000001883

PMID:28277328

Abstract

BACKGROUND

Neuropathic pain should be treated with drug combinations exhibiting multiple analgesic mechanisms of action because the mechanism of neuropathic pain involves multiple physiological causes and is mediated by multiple pathways. In this study, we defined the pharmacological interaction of BRL52537 (κ-opioid agonist), pregabalin (calcium channel modulator), AF 353 (P2X3 receptor antagonist), and A804598 (P2X7 receptor antagonist).

METHODS

Animal models of neuropathic pain were established by spinal nerve ligation (SNL) in male Sprague-Dawley rats, and responses to the mechanical stimulation using von Frey filaments were measured. Drugs were administered by intrathecal route and were examined for antiallodynic effects, and drug interactions were evaluated using isobolographic analysis. The mRNA expression levels of pain-related receptors in each spinal cord or dorsal root ganglion of naïve, SNL, and drug-treated SNL rats were evaluated using real-time polymerase chain reaction.

RESULTS

Intrathecal BRL52537, pregabalin, AF 353, and A804598 produced antiallodynic effects in SNL rats. In the drug combination studies, intrathecal coadministration of BRL52537 with pregabalin or A804598 exhibited synergistic interactions, and other drugs combinations showed additivity. The rank order of potency was observed as follows: BRL52537 + pregabalin > BRL52537 + A804598 > pregabalin + AF 353 > A804598 + pregabalin > BRL52537 + AF 353 > AF 353 + A804598. Real-time polymerase chain reaction indicated that alterations of P2X3 receptor and calcium channel mRNA expression levels were observed, while P2X7 receptor and κ-opioid receptor expression levels were not altered.

CONCLUSIONS

These results demonstrated that intrathecal combination of BRL52537, pregabalin, AF 353, and A804598 synergistically or additively attenuated allodynia evoked by SNL, which suggests the possibility to improve the efficacy of single-drug administration.

摘要

背景

神经性疼痛的机制涉及多种生理原因且由多种途径介导，因此应使用具有多种镇痛作用机制的药物组合进行治疗。在本研究中，我们确定了BRL52537（κ-阿片受体激动剂）、普瑞巴林（钙通道调节剂）、AF 353（P2X3受体拮抗剂）和A804598（P2X7受体拮抗剂）之间的药理相互作用。

方法

通过对雄性Sprague-Dawley大鼠进行脊神经结扎（SNL）建立神经性疼痛动物模型，使用von Frey细丝测量对机械刺激的反应。通过鞘内途径给药，检测药物的抗痛觉过敏作用，并使用等张线分析评估药物相互作用。使用实时聚合酶链反应评估未处理、SNL处理和药物处理的SNL大鼠的每个脊髓或背根神经节中疼痛相关受体的mRNA表达水平。

结果

鞘内注射BRL52537、普瑞巴林、AF 353和A804598可在SNL大鼠中产生抗痛觉过敏作用。在药物联合研究中，鞘内联合使用BRL52537与普瑞巴林或A804598表现出协同相互作用，其他药物组合表现为相加作用。观察到的效力顺序如下：BRL52537 + 普瑞巴林 > BRL52537 + A804598 > 普瑞巴林 + AF 353 > A804598 + 普瑞巴林 > BRL52537 + AF 353 > AF 353 + A804598。实时聚合酶链反应表明，观察到P2X3受体和钙通道mRNA表达水平发生改变，而P2X7受体和κ-阿片受体表达水平未改变。