Characterization of actions of the novel gabapentinoid drug mirogabalin on painful bladder hypersensitivity in rats with lipopolysaccharide-induced chronic cystitis

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-08-27 DOI:10.1016/j.lfs.2025.123942

Masaru Yoshizumi , Yutaka Kitano , Chizuko Watanabe , Shinobu Sakurada , Hirokazu Mizoguchi

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引用次数: 0

Abstract

Aims

Gabapentin reduces bladder pain and overactivity in lipopolysaccharide (LPS)-induced chronic cystitis in a rat model. This study evaluated the role of the spinal cord and the descending noradrenergic pathway in the effects of mirogabalin (MGB), a novel gabapentinoid drug on painful bladder hypersensitivity in this model.

Main methods

Chronic cystitis was induced in female Sprague–Dawley rats via repeated intravesical LPS instillation. von Frey filaments and continuous cystometry were used to assess bladder pain-related behaviors and micturition function, respectively. Changes in voltage-gated calcium channel α₂δ-1 subunits expression in the spinal dorsal horn (SDH) and locus coeruleus (LC) were analyzed using western blotting. Gabapentinoid effects were evaluated after systemic, intracerebroventricular, and intrathecal administration. Additionally, rats were treated with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) to deplete noradrenergic nerves, in order to investigate the involvement of the descending noradrenergic system in the LC.

Key findings

MGB, as well as other gabapentinoids, reduced LPS-induced increases in cystitis-related pain and voiding frequency after systemic, intrathecal, or intracerebroventricular administration. Notably, MGB exhibited longer-lasting analgesic effects than other gabapentinoids. LPS-induced cystitis rats showed up-regulation of the α₂δ-1 subunit in the SDH and LC. Pretreatment with DSP-4 reversed the analgesic effects of gabapentinoids but did not affect their inhibitory effect on micturition.

Significance

The therapeutic effects of MGB in hypersensitivity associated with cystitis, similar to other gabapentinoids, are mediated by spinal and supraspinal actions, likely via the α₂δ-1 subunit. Additionally, MGB exerts its analgesic effects through a supraspinal mechanism via the descending noradrenergic pathway, whereas a different mechanism regulates micturition.

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新型加巴喷丁类药物米罗巴林对脂多糖诱导的慢性膀胱炎大鼠膀胱疼痛过敏的作用

目的：加巴喷丁减轻脂多糖（LPS）诱导的慢性膀胱炎大鼠模型膀胱疼痛和过度活动。本研究在该模型中评估了脊髓和降去甲肾上腺素能通路在新型加巴喷丁类药物米罗巴林（MGB）对疼痛性膀胱超敏反应的影响中的作用。主要方法通过反复灌胃LPS诱导雌性sd大鼠慢性膀胱炎。采用von Frey细丝法和连续膀胱术分别评估膀胱疼痛相关行为和排尿功能。western blotting分析了大鼠脊背角（SDH）和蓝斑（LC）中电压门控钙通道α2δ-1亚基表达的变化。在全身、脑室内和鞘内给药后评估加巴喷丁的效果。此外，给大鼠注射N-（2-氯乙基）-N-乙基-2-溴苄胺（spd -4）以消耗去甲肾上腺素能神经，以研究去甲肾上腺素能下降系统在LC中的作用。主要发现smgb以及其他加巴喷丁类药物，在全身、鞘内或脑室内给药后，减少了lps引起的膀胱炎相关疼痛和排尿频率的增加。值得注意的是，MGB比其他加巴喷丁类具有更持久的镇痛作用。lps诱导的膀胱炎大鼠SDH和LC中α2δ 1亚基上调。用DSP-4预处理可逆转加巴喷丁类药物的镇痛作用，但不影响其对排尿的抑制作用。与其他加巴喷丁类药物类似，MGB对膀胱炎相关超敏反应的治疗作用可能通过α2δ-1亚基介导，由脊柱和棘上作用介导。此外，MGB通过降去肾上腺素能通路的椎管上机制发挥其镇痛作用，而调节排尿的机制不同。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.