Activation of spinal extracellular signal-regulated kinases (ERK) 1/2 is associated with the development of visceral hyperalgesia of the bladder

Abstract

Activation of extracellular signal-regulated kinases (ERK) 1/2 in dorsal horn neurons is important for the development of somatic hypersensitivity and spinal central sensitization after peripheral inflammation. However, data regarding the roles of spinal ERK1/2 in the development of visceral hyperalgesia are sparse. Here we studied the activation of ERK1/2 in the lumbosacral spinal cord following innocuous and noxious distention of the inflamed (cyclophosphamide- treated) and non-inflamed urinary bladder in mice. We also correlated the spinal ERK1/2 activation to distention-evoked bladder nociception as quantified by the abdominal visceromotor response (VMR). Cyclophosphamide treatment (bladder inflammation) evoked increased bladder hyperalgesia and allodynia to bladder distention, as evident from an upward and leftward shift of the VMR stimulus-response curve compared to that of non-inflamed mice. Development of bladder hyperalgesia was associated with robust enhancement of ERK1/2 activation in the dorsal horn and deeper laminae bilaterally in the L6-S1 spinal cord. Functional blockade of spinal ERK1/2 activity via intrathecal administration of the upstream MEK inhibitor U0126 attenuated distention-evoked bladder nociception, and caused a significant downward shift of the VMR stimulus-response curve. In summary, we have provided functional and immunohistochemical evidence that activation of lumbosacral spinal ERK1/2 is associated with the development of primary visceral (bladder) hyperalgesia. Our results suggest that aberrant processing of visceral nociceptive information at the level of the lumbosacral spinal cord via activation of ERK1/2 signaling may contribute to chronic bladder pain in the context of inflammation.

Animal Models of Urologic Chronic Pelvic Pain Syndromes: Findings From the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network

“…5 UTI-treated mice and CYP-treated mice also show VMR magnitudes (a surrogate measure of bladder distention evoked pain) about twice as high compared to their respective controls. 6,17 The percent changes in urinary frequency in the CYP model 13 and the two stress models 22,24 are also similar to those observed in IC/BPS patients. 5 …”

“…During phasic bladder distention, an increase of abdominal VMR or electromyographic signals corresponds to increased guarding and abdominal withdrawal when the animal experiences bladder pain from the distention. The VMR shows a dose-response relation with bladder distention pressure, 6 which mimics the hypersensitivity (hyperalgesia) to bladder distention observed in IC/BPS patients. 5 The VMR is facilitated by inflammation and inhibited by analgesics.…”

“…5 In rodents, this was examined with the bladder distention and VMR paradigm (described in detail in Figures 1A–B). 6 VMR was used as a surrogate measure of nociception (pain) evoked by bladder distention. During phasic bladder distention, an increase of abdominal VMR or electromyographic signals corresponds to increased guarding and abdominal withdrawal when the animal experiences bladder pain from the distention.…”

“…The following proposed UCPPS models were phenotyped by MAPP Network investigators with respect to bladder/pelvic nociception (pain) and urinary frequency: (a) animals monitored during/following transient urinary tract infection (acute UTI mice, and mice with post-UTI pain), 15–17 (b) animals infected with the pseudorabies virus (PRV mice), 11,18,19 (c) animals exhibiting cyclophosphamide-induced cystitis (CYP mice), 6 (d) animals expressing urothelial OVA (URO-OVA mice), 20 (e) animals expressing urothelial MCP-1 (URO-MCP-1 mice). This list does not represent an exhaustive list of potential UCPPS models or intends to exclude other models; rather this list represents the models used by MAPP Network investigators in their mechanistic studies of UCPPS.…”

Beyond a Simple Anesthetic Effect: Lidocaine in the Diagnosis and Treatment of Interstitial Cystitis/bladder Pain Syndrome

“…7 This may represent a disease entity having a primary source elsewhere, such as myofascial pain, 8,9 with the colocated spinal cord dorsal horn instigating bladder symptoms via complex and powerful mechanisms, which we now understand as peripheral and central sensitization. 10 Lidocaine is a common local anesthetic (LA) agent that is also used in a variety of chronic and persistent pain syndromes, including treatment of IC/BPS. This review will present the published clinical experience with intravesical lidocaine, as well as briefly review the antiinflammatory effects of lidocaine pertinent to IC.…”