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Spinal blockage of P / Q ‐ or N ‐type voltage‐gated calcium channels modulates functional and symptomatic changes related to haemorrhagic cystitis in mice
Author(s) -
Silva R B M,
Sperotto N D M,
Andrade E L,
Pereira T C B,
Leite C E,
Souza A H,
Bogo M R,
Morrone F B,
Gomez M V,
Campos M M
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12966
Subject(s) - trpv1 , pharmacology , chemistry , voltage dependent calcium channel , nociception , hyperalgesia , antagonist , resiniferatoxin , calcium , receptor , endocrinology , anesthesia , medicine , transient receptor potential channel , biochemistry
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 .