Endogenous kappa-opioid receptor systems inhibit hyperalgesia associated with localized peripheral inflammation.
Peripheral inflammation evokes functional and biochemical changes in the periphery and spinal cord which result in central sensitization and hypersensitivity. Inhibitory control systems from the rostral ventromedial medulla (RVM) are also activated. The present study investigates whether endogenous kappa-opioid receptor (KOPr) systems contribute to these neuroadaptations. Inflammation was induced by intraplantar injection of complete Freund's adjuvant (CFA) into one hindpaw. Mechanical and thermal thresholds were determined using the Von Frey and radiant heat tests, respectively. KOPr gene deletion in mice or systemic administration of the long-acting KOPr antagonist, norbinaltorphimine (norBNI) significantly exacerbated mechanical and thermal hypersensitivity of the ipsilateral, inflamed paw. Thermal and mechanical thresholds of the non-inflamed, contralateral hindpaw were unaffected by CFA treatment. However, gene deletion as well as norBNI treatment resulted in mechanical, but not thermal hypersensitivity of the non-inflamed paw. Similar results were obtained when norBNI was administered intrathecally or into the RVM in rats. These data demonstrate a previously unrecognized role of endogenous KOPr systems in inhibiting hyperalgesia during inflammation. Furthermore, they demonstrate that decreased KOPr activity in either the spinal cord or RVM not only enhances mechanical and thermal hyperalgesia of the inflamed limb but also leads to an unmasking of mechanical hyperalgesia at a site remote from inflammation. The differential effects of KOPr antagonism on mechanical versus thermal thresholds for the non-inflamed paw support the notion that distinct neuroanatomical or neurochemical mechanisms modulate the processing of thermal versus mechanical stimuli.
Schepers
R J
RJ
University of Maryland School of Medicine, 660 West Redwood Street, Baltimore, MD 21201, USA Integrative Neuroscience Section, Behavioral Neuroscience Branch, National Institutes of Health/National Institute on Drug Abuse Intramural Research Program, 333 Cassell Drive, Baltimore, MD 21224, USA.
Mahoney
Janet Lynn
JL
Gehrke
Brenda Jean
BJ
Shippenberg
Toni Shaun
TS
D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D006930:Hyperalgesia / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*; D007249:Inflammation / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000502:physiology*
D000701:Analgesics, Opioid; D017473:Receptors, Opioid, kappa