Ceftriaxone inhibits stress‐induced bladder hyperalgesia and alters cerebral micturition and nociceptive circuits in the rat: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome research network study

• Published in: Neurourology and urodynamics 2020-08, Vol.39 (6), p.1628-1643
• Main Authors: Holschneider, Daniel P., Wang, Zhuo, Chang, Huiyi, Zhang, Rong, Gao, Yunliang, Guo, Yumei, Mao, Jackie, Rodriguez, Larissa V.
• Format: Article
• Language: English
• Subjects: animal model; Animals; Antibiotics; Bladder; Blood flow; Brain; Brain mapping; Brain slice preparation; Ceftriaxone; Ceftriaxone - pharmacology; Ceftriaxone - therapeutic use; Cerebral blood flow; Circuits; Cystitis; Cystitis, Interstitial - drug therapy; Cystitis, Interstitial - physiopathology; Disease Models, Animal; Distension; Female; glutamate; Glutamatergic transmission; Hyperalgesia; Hyperalgesia - drug therapy; Hyperalgesia - physiopathology; Hypersensitivity; Intravenous administration; Mapping; micturition; Neural Pathways - drug effects; Neural Pathways - physiopathology; Nociception - drug effects; Pain perception; painful bladder syndrome/interstitial cystitis; Pelvic Pain - drug therapy; Pelvic Pain - physiopathology; Rats; Rats, Inbred WKY; Regions; Somatosensory cortex; Thalamus; Urination; Urination - drug effects; water avoidance stress
• ISSN: 0733-2467; 1520-6777
• DOI: 10.1002/nau.24424

Aims Emotional stress plays a role in the exacerbation and development of interstitial cystitis/bladder pain syndrome (IC/BPS). Given the significant overlap of brain circuits involved in stress, anxiety, and micturition, and the documented role of glutamate in their regulation, we examined the effects of an increase in glutamate transport on central amplification of stress‐induced bladder hyperalgesia, a core feature of IC/BPS. Methods Wistar‐Kyoto rats were exposed to water avoidance stress (WAS, 1 hour/day x 10 days) or sham stress, with subgroups receiving daily administration of ceftriaxone (CTX), an activator of glutamate transport. Thereafter, cystometrograms were obtained during bladder infusion with visceromotor responses (VMR) recorded simultaneously. Cerebral blood flow (CBF) mapping was performed by intravenous injection of [14C]‐iodoantipyrine during passive bladder distension. Regional CBF was quantified in autoradiographs of brain slices and analyzed in three dimensional reconstructed brains with statistical parametric mapping. Results WAS elicited visceral hypersensitivity during bladder filling as demonstrated by a decreased pressure threshold and VMR threshold triggering the voiding phase. Brain maps revealed stress effects in regions noted to be responsive to bladder filling. CTX diminished visceral hypersensitivity and attenuated many stress‐related cerebral activations within the supraspinal micturition circuit and in overlapping limbic and nociceptive regions, including the posterior midline cortex (posterior cingulate/anterior retrosplenium), somatosensory cortex, and anterior thalamus. Conclusions CTX diminished bladder hyspersensitivity and attenuated regions of the brain that contribute to nociceptive and micturition circuits, show stress effects, and have been reported to demonstrated altered functionality in patients with IC/BPS. Glutamatergic pharmacologic strategies modulating stress‐related bladder dysfunction may be a novel approach to the treatment of IC/BPS.