title: The Glt1 glutamate receptor mediates the establishment and perpetuation of chronic visceral pain in an animal model of stress-induced bladder hyperalgesia.
abstract: Psychological stress exacerbates interstitial cystitis/bladder pain syndrome (IC/BPS), a lower urinary tract pain disorder characterized by increased urinary frequency and bladder pain. Glutamate (Glu) is the primary excitatory neurotransmitter modulating nociceptive networks. Glt1, an astrocytic transporter responsible for Glu clearance, is critical in pain signaling termination. We sought to examine the role of Glt1 in stress-induced bladder hyperalgesia and urinary frequency. In a model of stress-induced bladder hyperalgesia with high construct validity to human IC/BPS, female Wistar-Kyoto (WKY) rats were subjected to 10-day water avoidance stress (WAS). Referred hyperalgesia and tactile allodynia were assessed after WAS with von Frey filaments. After behavioral testing, we assessed Glt1 expression in the spinal cord by immunoblotting. We also examined the influence of dihydrokainate (DHK) and ceftriaxone (CTX), which downregulate and upregulate Glt1, respectively, on pain development. Rats exposed to WAS demonstrated increased voiding frequency, increased colonic motility, anxiety-like behaviors, and enhanced visceral hyperalgesia and tactile allodynia. This behavioral phenotype correlated with decreases in spinal Glt1 expression. Exogenous Glt1 downregulation by DHK resulted in hyperalgesia similar to that following WAS. Exogenous Glt1 upregulation via intraperitoneal CTX injection inhibited the development of and reversed preexisting pain and voiding dysfunction induced by WAS. Repeated psychological stress results in voiding dysfunction and hyperalgesia that correlate with altered central nervous system glutamate processing. Manipulation of Glu handling altered the allodynia developing after psychological stress, implicating Glu neurotransmission in the pathophysiology of bladder hyperalgesia in the WAS model of IC/BPS.
authors.affiliation: Department of Urology, The David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: A Lenore
authors.identifier: 0000-0003-4192-7649
authors.initials: AL
authors.lastname: Ackerman
authors.affiliation: Department of Urology, San Antonio Military Medical Center (SAMMC), Fort Sam Houston, Texas.
authors.forename: Forrest C
authors.initials: FC
authors.lastname: Jellison
authors.affiliation: Section of Urology and Renal Transplantation, Virginia Mason Medical Center, Seattle, Washington.
authors.forename: Una J
authors.initials: UJ
authors.lastname: Lee
authors.affiliation: Center for the Neurobiology of Stress, The David Geffen School of Medicine at UCLA, Los Angeles, California; and.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bradesi
authors.affiliation: Departments of Urology and Obstetrics and Gynecology, University of Southern California, Los Angeles, California lrodriguez@med.usc.edu.
authors.forename: Larissa V
authors.initials: LV
authors.lastname: Rodríguez
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002443:Ceftriaxone / Q000494:pharmacology; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D006930:Hyperalgesia / Q000378:metabolism* / Q000503:physiopathology; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*; D001743:Urinary Bladder / Q000503:physiopathology*; D059265:Visceral Pain / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D027342:Excitatory Amino Acid Transporter 2; C493395:Slc1a2 protein, rat; C020889:dihydrokainic acid; D002443:Ceftriaxone; D007608:Kainic Acid
keywords: bladder pain syndrome; ceftriaxone; glutamate processing; hyperalgesia; interstitial cystitis