Naloxone could limit morphine hypersensitivity: Considering the molecular mechanisms

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM Neuropeptides Pub Date : 2023-08-01 DOI:10.1016/j.npep.2023.102345

Mojgan Baratzadeh , Samira Danialy , Shima Abtin , Homa Manaheji

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Abstract

Background

Naloxone has been used as an opioid antagonist to prevent multiple adverse side effects of opioid-like tolerance and hyperalgesia. This study has investigated naloxone combined with morphine to limit pain hypersensitivity. In addition, the expression of brain-derived neurotrophic factor (BDNF) and K⁺ Cl⁻ cotransporter2 (KCC2) were also studied.

Methods

Forty-eight adult male Wistar rats (180–220 g) were divided into eight groups, with six rats in each group. Rats were divided into two tolerance and hyperalgesia groups; the sham group, the morphine group, the treatment group (naloxone along with morphine), and the sham group (naloxone along with saline) for eight consecutive days. Tail-flick test was performed on days 1, 5, and 8, and the plantar test on days 1 and 10. On days 8 and 10, the lumbar segments of the spinal cord were collected, and BDNF and KCC2 expression were analyzed using western blotting and immunohistochemistry, respectively.

Results

Results showed that tolerance and hyperalgesia developed following eight days of repeated morphine injection. BDNF expression significantly increased, but KCC2 was downregulated. Co-administration of naloxone and morphine decreased tolerance and hyperalgesia by decreasing BDNF and increasing KCC2 expression, respectively.

Conclusion

This study suggests that BDNF and KCC2 may be candidate molecules for decreased morphine tolerance and hyperalgesia.

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纳洛酮可以限制吗啡过敏:考虑分子机制

背景纳洛酮已被用作阿片类拮抗剂，以预防阿片类耐受和痛觉过敏的多种副作用。本研究研究了纳洛酮与吗啡联合应用以限制疼痛超敏反应。此外，还研究了脑源性神经营养因子（BDNF）和K+Cl−协同转运蛋白2（KCC2）的表达。方法48只成年雄性Wistar大鼠（180～220g）分为8组，每组6只。将大鼠分为耐受组和痛觉过敏组；假手术组、吗啡组、治疗组（纳洛酮加吗啡）和假手术组（纳洛酮加生理盐水）连续8天。在第1、5和8天进行甩尾试验，在第1和10天进行足底试验。在第8天和第10天，收集脊髓的腰段，并分别使用蛋白质印迹和免疫组织化学分析BDNF和KCC2的表达。结果重复注射吗啡8天后，出现耐受性和痛觉过敏。BDNF表达显著增加，但KCC2表达下调。纳洛酮和吗啡联合给药分别通过降低BDNF和增加KCC2的表达来降低耐受性和痛觉过敏。结论BDNF和KCC2可能是降低吗啡耐受和痛觉过敏的候选分子。

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来源期刊

Neuropeptides 医学-内分泌学与代谢

CiteScore

5.40

自引率

6.90%

发文量

审稿时长

>12 weeks

期刊介绍： The aim of Neuropeptides is the rapid publication of original research and review articles, dealing with the structure, distribution, actions and functions of peptides in the central and peripheral nervous systems. The explosion of research activity in this field has led to the identification of numerous naturally occurring endogenous peptides which act as neurotransmitters, neuromodulators, or trophic factors, to mediate nervous system functions. Increasing numbers of non-peptide ligands of neuropeptide receptors have been developed, which act as agonists or antagonists in peptidergic systems. The journal provides a unique opportunity of integrating the many disciplines involved in all neuropeptide research. The journal publishes articles on all aspects of the neuropeptide field, with particular emphasis on gene regulation of peptide expression, peptide receptor subtypes, transgenic and knockout mice with mutations in genes for neuropeptides and peptide receptors, neuroanatomy, physiology, behaviour, neurotrophic factors, preclinical drug evaluation, clinical studies, and clinical trials.