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.

The role of C‐fibers in the development of chronic psychological stress induced enhanced bladder sensations and nociceptive responses: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study

“…In addition, a longer VMR duration in WAS rats represents a longer sensory/pain response to bladder stimuli. A lower sensory threshold may explain the previously documented increases in urinary frequency in this animal model . This is consistent with our previous publications, which demonstrates that the increased urinary frequency in rats exposed to WAS is associated with bladder hyperalgesia .…”

“…A lower sensory threshold may explain the previously documented increases in urinary frequency in this animal model. 7,8,13 This is consistent with our previous publications, which demonstrates that the increased urinary frequency in rats exposed to WAS is associated with bladder hyperalgesia. 8 The WAS-induced bladder hypersensitivity is similar to other reports regarding different stress animal models.…”

“…We have previously published the effects of WAS on voiding and water intake . The main goal of the present study was to evaluate the urinary function of these animals by CMG.…”

“…We have previously published the effects of WAS on voiding and water intake. 7,8,13 The main goal of the present study was to evaluate the urinary function of these animals by CMG. In the present study, we chose VMR as an indicator for WAS-induced bladder dysfunction and hypersensitivity.…”

P2X3 receptor‐mediated visceral hyperalgesia and neuronal sensitization following exposure to PTSD‐like stress in the dorsal root ganglia of rats

“…A recent study using an animal model of stress‐induced hyperalgesia revealed that exogenous glial glutamate transporter‐1 GLT‐1 upregulation via intraperitoneal CTX injection inhibited development and reversed pre‐existing pain and voiding dysfunction induced by water avoidance stress . Our studies also showed that GLT‐1 overexpression attenuates visceral nociception of the VMR to bladder distension and both local irritant‐induced and cross‐organ‐sensitized VMR to bladder distension or by neonatal colonic insult .…”