Life sciences · 2025
Characterization of actions of the novel gabapentinoid drug mirogabalin on painful bladder hypersensitivity in rats with lipopolysaccharide-induced chronic cystitis.
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Yoshizumi Masaru, Kitano Yutaka, Watanabe Chizuko, Sakurada Shinobu, Mizoguchi Hirokazu
Аннотация
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.
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.