• Henry H Lai, Chang-Shen Qiu, Lara W Crock, MoralesMaria Elena PMEP, Timothy J Ness, and Robert W Gereau.
• Department of Surgery, Division of Urologic Surgery, Washington University School of Medicine, St. Louis, MO, USA Department of Surgery, St. Louis Veterans Affairs Medical Center, St. Louis, MO, USA Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL, USA.
• Pain. 2011 Sep 1; 152 (9): 2117-2124.

AbstractActivation 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 after innocuous and noxious distention of the inflamed (cyclophosphamide-treated) and noninflamed 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 with that of noninflamed 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.Published by Elsevier B.V.

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