Author ORCID Identifier

0000-0002-3900-2973

Date of Graduation

12-2018

Document Type

Dissertation (PhD)

Program Affiliation

Neuroscience

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Edgar T. Walters, Ph.D.

Committee Member

Carmen W. Dessauer, Ph.D.

Committee Member

Annemieke Kavelaars, Ph.D.

Committee Member

Patrick M. Dougherty, Ph.D.

Committee Member

Shane R. Cunha, Ph.D.

Abstract

Postsurgical and neuropathic pain are each clinically common, and often associated with ongoing pain. Ongoing pain has been linked to ongoing activity (OA) in human C-fiber nociceptors. Preclinical studies using rodent neuropathic models have concentrated on allodynia driven by OA generated in non-nociceptive Aβ fibers, but little attention has been paid to postsurgical pain in sham controls or to C-fiber nociceptor OA promoting ongoing pain.

Operant assays that reveal negative motivational and cognitive aspects of voluntary pain-related behavior may be particularly sensitive to pain-related alterations. In the mechanical conflict (MC) test, rodents can freely choose to escape from a brightly lit chamber by crossing sharp probes. Most studies employing the MC test habituate rodents to the device and measure the latency to escape the bright light. We found reducing habituation caused rats to repeatedly return to the light chamber when probes were absent, presumably as part of their exploratory behavior. We asked whether combining motivations to avoid the bright light and to explore the device would reveal a conflicting, pain-related reluctance of rats to cross noxious probes. Rats with a thoracic spinal cord injury (SCI), lumbar spinal nerve transection, or chronic constriction injury of the sciatic nerve, as well as their sham controls, exhibited heightened pain-avoidance behavior compared to uninjured controls. These findings have important implications for investigations into behavioral and neuronal alterations contributing to postsurgical and neuropathic pain.

Many C-fiber nociceptors generate OA in vivo in rats with SCI and ongoing pain. Probable nociceptors continue to generate OA in vitro after dissociation. We used whole-cell recordings from isolated dorsal root ganglion neurons and novel algorithms that analyze irregular changes in membrane potential (MP) to define neurophysiological alterations underlying SCI-induced nociceptor OA. In a distinct type of probable nociceptor, SCI caused 3 chronic alterations that promote OA: 1) depolarization of resting MP, 2) reduction in the voltage threshold for action potential generation, and 3) enhancement of depolarizing spontaneous fluctuations (DSFs) in MP. In vitro modeling of acute inflammation by combining serotonin with artificial depolarization also potentiated DSFs and OA. These findings reveal nociceptor specializations for generating OA during ongoing pain.

Keywords

postoperative pain, spontaneous pain, pain-avoidance behavior, nociceptor, spontaneous activity, neural injury, spinal cord injury, inflammation, membrane potential, depolarizing spontaneous fluctuations

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