Persistent Mechanical Hypersensitivity in Rats: Biobehavioral Effects

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DESCRIPTION (provided by applicant): An alarming 26% of Americans report pain persisting for more than one day in the previous month and 42% of these individuals indicated that their pain lasted more than one year. Despite the enormous scope of the problem of chronic pain, there is minimal understanding or study of the causal pathways in the transition from acute pain conditions to persistent pain syndromes. Clinical models of persistent pain indicate large variability in the experience of acute pain and the course of chronic pain development, yet pre-clinical models demonstrate small variability in the experience of acute pain or the development of persistent pain. The long- term goal of this new collaborative effort is to systematically exploit an established pre-clinical model that offers the opportunity to study susceptibility to and resilience against persistent pain development. Our overarching hypothesis is that biobehavioral factors such as sleep disruption and altered hypothalamic-pituitary-adrenal (HPA) axis stress responsivity both contribute to and result from the development of persistent pain conditions. We propose to exploit the sciatic inflammatory neuritis (SIN) model, advantageous for separating the surgical insult from pain initiation, and the controllability and variability of the zymosan dose as pain initiator, to address two specific aims in male rats: (1) To determine the impact of sleep disruption on the development of persistent inflammation-induced mechanical hypersensitivity. The occurrence and severity of persistent inflammation- induced mechanical hypersensitivity will be compared between rats remaining undisturbed versus those whose sleep attempts are disrupted by gentle handling during the first 6 h after light onset each day from the day prior to the first SIN catheter zymosan infusion through the 10th and final daily zymosan infusion. (2) To determine the impact of HPA axis responsivity on the development of persistent inflammation-induced mechanical hypersensitivity and its consequent effects on sleep-wake behavior. The inbred HPA axis hyporesponsive Lewis and HPA axis hyper-responsive Fischer 344 rats, and the outbred Sprague Dawley rat will be compared for the occurrence and severity of inflammation-induced persistent mechanical hypersensitivity as well as its impact on sleep-wake behavior. The significance of the proposed study relates to the pervasiveness of chronic pain, the high association of pain and sleep disruption, and the paucity of previous experimental work identifying susceptibility and resilience factors related to chronic pain development. This study is innovative for employing an ecologically valid sleep deprivation paradigm, and utilizing genetically different rat strains to determine the contributions of HPA axis responsivity to persistent mechanical hypersensitivity development and consequent sleep alterations. The successful conduct of the proposed study will provide a platform upon which to build studies focusing on functional outcomes in addition to sleep such as locomotion, mood, and early life pain experiences. The addition of females is a vital next step. PUBLIC HEALTH RELEVACE The prevalence of chronic pain was recently reported to be an alarming 48%, and pain of primarily neuropathic origin was reported to be 8%. Despite the enormous scope of the problem of chronic pain, there is minimal understanding or study of the causes of the transition from acute pain to long-lasting chronic pain. The relevance of the proposed study to human health is the goal to discern what factors (e.g., sleep disruption, biological responses to stress and anxiety) increase one s risk to develop chronic pain.