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ENDOCANNABINOID SIGNALING IN THE DORSAL PERIAQUEDUCTAL GRAY INFLUENCES THE DEVELOPMENT OF NEUROPATHIC PAIN
Author(s) -
Dean Caron,
Hillard Cecilia,
Seagard Jeanne,
Hopp Francis,
Hogan Quinn
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1234.1
Subject(s) - endocannabinoid system , periaqueductal gray , sni , hyperalgesia , nerve injury , nociception , anesthesia , fatty acid amide hydrolase , neuropathic pain , medicine , cannabinoid receptor , chemistry , central nervous system , midbrain , receptor , agonist , biochemistry , hydrolysis , acid hydrolysis
Descending endocannabinoid modulation of sensory pathways from the midbrain dorsal periaqueductal gray (dPAG) contributes to the relief of neuropathic pain. Endocannabinoids also activate the sympathetic nervous system through actions at cannabinoid 1 receptors (CB1Rs) in the dPAG. These studies were designed to determine if endocannabinoid signaling in the dPAG influences the development of pain and autonomic changes following nerve injury. Male Sprague‐Dawley rats (320–340 gm) were implanted with telemetric transducers to monitor blood pressure. After one week, either a neuropathic pain model of spared nerve injury (SNI) or sham surgery was performed. Heart rate (HR) and HR variability were derived from blood pressure recordings taken on days 5–7 following implantation surgery and on days 1,3,7,10,14 and 21 following SNI or sham surgery. On these days, rats were also tested for hyperalgesia responses to noxious mechanical stimulation of the hindpaw. Animals that demonstrated a hyperalgesia response rate >20% on day 21 were considered hyperalgesic. Brains were removed on day 21 post SNI/sham, and the dPAG region was excised and quick‐frozen in liquid nitrogen. Real time RT‐PCR was performed to analyze the tissue samples for mRNA expression of the endocannabinoid metabolic enzymes fatty acid amide hydrolase (FAAH) and for CB1Rs. Transcript levels were plotted against blood pressure, HR, autonomic activity, and hyperalgesia response rate for regression analysis to determine correlations. Over 21 days, a range of hyperalgesia responses from 0–80 % developed in SNI rats and no hyperalgesia developed in sham animals. Hyperalgesia animals had a significantly depressed low frequency/high frequency (LF/HF) ratio of HR variability, an indicator of sympatho‐vagal balance and higher HF power, indicative of vagal tone. The hyperalgesia response rate was correlated, and the LF/HF power was inversely correlated, to amounts of FAAH mRNA. Reduced FAAH expression in non‐hyperalgesia animals would be expected to result in increased concentrations of the endocannabinoid, anandamide. Transcript levels for CB1R were unchanged. Animals with hyperalgesia showed a significantly greater decrease in HR over 21 days than those without, while blood pressure remained unchanged. These data suggest that increased endocannabinoid signaling in the dPAG influences autonomic nerve activity and prevents the development of neuropathic pain. Support or Funding Information Supported by Veterans Affairs BX001863 (QHH, CD) and the Research and Education Component of the Advancing a Healthier Wisconsin Endowment at MCW (CJH).