Spinal blockage of P / Q ‐ or N ‐type voltage‐gated calcium channels modulates functional and symptomatic changes related to haemorrhagic cystitis in mice

Background and Purpose Spinal voltage‐gated calcium channels (VGCCs) are pivotal regulators of painful and inflammatory alterations, representing attractive therapeutic targets. We examined the effects of epidural administration of the P / Q ‐ and N ‐type VGCC blockers T x3‐3 and P hα1β, respectively, isolated from the spider P honeutria nigriventer , on symptomatic, inflammatory and functional changes allied to mouse cyclophosphamide ( CPA )‐induced haemorrhagic cystitis ( HC ). The effects of P . nigriventer ‐derived toxins were compared with those displayed by MVIIC and MVIIA , extracted from the cone snail Conus   magus . Experimental Approach HC was induced by a single i.p. injection of CPA (300 mg·kg –1 ). Dose‐ and time‐related effects of spinally administered P /Q and N ‐type VGCC blockers were assessed on nociceptive behaviour and macroscopic inflammation elicited by CPA . The effects of toxins were also evaluated on cell migration, cytokine production, oxidative stress, functional cystometry alterations and TRPV1 , TRPA1 and NK 1 receptor mRNA expression. Key Results The spinal blockage of P / Q ‐type VGCC by T x3‐3 and MVIIC or N ‐type VGCC by Phα1β attenuated nociceptive and inflammatory events associated with HC , including bladder oxidative stress and cytokine production. CPA produced a slight increase in bladder TRPV1 and TRPA1 mRNA expression, which was reversed by all the toxins tested. Noteworthy, P hα1β strongly prevented bladder neutrophil migration, besides HC ‐related functional alterations, and its effects were potentiated by co‐injecting the selective NK 1 receptor antagonist CP ‐96345. Conclusions and Implications Our results shed new light on the role of spinal P / Q and N ‐type VGCC in bladder dysfunctions, pointing out P hα1β as a promising alternative for treating complications associated with CPA ‐induced HC .