My commitment to pain research is a direct result of caring for very young children recovering from cardiac surgery without benefit of adequate analgesia. It has been my goal to causally demonstrate that adequate pain management is a matter of physiologic necessity. My dissertation and early career research studies in rats show that adequate provision of perioperative analgesia statistically and biologically significantly attenuate the in vivo immunosuppressive and tumor-enhancing effects of experimental laparotomy and normalize exploratory behavior. Inclusion of females in my experimental designs is a mainstay. Discovering a means by which to investigate the long-term consequences of repeated early neonatal pain experiences over the lifecourse enabled me to focus on the very young, yielding evidence that repeated paw needle pokes in the rat pup result in altered emotionality and greater nociceptive behavior scores in response to hind paw formalin injection, a commonly used tonic inflammatory pain stimulus. Females fared worse in this latter pain finding at maturity. In my recent efforts using preclinical models to study biobehavioral susceptibility to the development of persistent pain, findings that (1) sleep restriction increases susceptibility to hind paw mechanical hypersensitivity in both controls and animals with sciatic inflammatory neuritis and (2) repeated social defeat, a preclinical model of depression, appears to increase nociceptive behavior scores in response to hind paw formalin injection have greatly contributed to my sense of urgency to add the domain of sleep to my program of pain research. My long-term goal is to study factors that render the organism susceptible to persistent pain development over the lifecourse and possible mechanisms underlying these relationships. The factors of focus are pain, sleep and depression, rarely considered as a triad of comorbidity. My short-term goal for the duration of this 12-month Career Development Award is to build a substantial knowledge base regarding sleep from conceptualization to instrumentation, analysis and interpretation, to enable its full incorporation into my program of biobehavioral pain research. The key elements of this plan are to complete a foundational polysomnography course, and develop a working knowledge of the sleep literature relevant to my long-term research goal. The greatest portion of my committed 40% effort is to be dedicated to developing proficiency in electroencephalogram (EEG)/electromyogram (EMG) electrode and telemetry unit implantation, quantification of arousal states and EEG spectral analysis, and statistical methods in the analysis of sleep outcomes. The research environment at Johns Hopkins University is very strong. The School of Nursing leadership enthusiastically endorses this career development opportunity and is committed to the release plan we have devised. A great strength is proposed mentor Dr. Mark Opp, a renowned expert in rodent sleep with whom I have a history of collaboration and mentoring. He is committed as mentor to enable my career development as proposed herein, assured full access to his laboratory during the three proposed visits, and confirmed his availability for consultation as frequently as necessary. Sleep and depression are bidirectionally comorbid such that disrupted sleep is associated with increased risk for depression and depression is associated with disrupted sleep. The purpose of the proposed pilot project is to causally evaluate the impact of a promising preclinical model of depression, repeated exposures to social defeat, on sleep and neuroendocrine and immune function in Fischer 344 (F344) female and male rats. After full recovery from EEG/EMG transmitter implantation, 40 female and male rats undergo 12 60 min exposures to either social defeat or a novel cage distributed over a 4-week period, and then remain in their home cage for two weeks. A social defeat exposure consists of placing the F344 male intruder into the resident cage of a Long Evans female-male pair, or the F344 female intruder into the resident cage immediately following removal of the Long Evans male. Immediately after defeat of the intruder, a protective mesh barrier is placed over the intruder within the resident cage for the remainder of the intrusion period. Novel cage animals are placed in an empty cage during this time. EEG/EMG recordings are to be continuous, with sampling before social defeat is initiated, before and after each social defeat / novel cage exposure, and during the 2-week rest period. Sleep outcomes include arousal state, latencies to state and sleep-state specific EEG spectral profiles. Sucrose 1% versus plain water preference is monitored daily from 1 week prior to social defeat / novel cage exposure through euthanasia to indicate anhedonia. Plasma corticosterone levels are to be assessed at preoperative baseline, immediately after the first and final exposure to social defeat / novel cage, and at euthanasia. Additional outcomes at euthanasia include pro-inflammatory cytokine levels, and dexamethasone suppression of lipopolysaccharide-induced pro-inflammatory cytokine production in whole blood. General linear mixed models and Univariate ANOVA are to be used as appropriate for analysis. Aspects of significance include long- term sleep measurement, neuroendocrine and immune outcomes, and inclusion of females.
Disrupted sleep, pain affect substantial numbers of individuals and are well known to be co-occurring. The relevance of the proposed Career Development Award is to build a substantial knowledge base regarding sleep in order to add this domain to my program of biobehavioral pain research. The relevance of this proposed award to human health is to discern the contributions and consequences of disrupted sleep as it relates to the development of persistent pain.
| Page, Gayle G; Opp, Mark R; Kozachik, Sharon L (2016) Sex differences in sleep, anhedonia, and HPA axis activity in a rat model of chronic social defeat. Neurobiol Stress 3:105-113 |
