Inhibition of inflammatory pain by CRF at peripheral, spinal and supraspinal sites: involvement of areas coexpressing CRF receptors and opioid peptides.
There is conflicting evidence on the antinociceptive effects of corticotropin-releasing factor (CRF) along the neuraxis of pain transmission and the responsible anatomical sites of CRF's action at the level of the brain, spinal cord and periphery. In an animal model of tonic pain, that is, Freunds complete adjuvant (FCA) hindpaw inflammation, we systematically investigated CRF's ability to modulate inflammatory pain at those three levels of pain transmission by algesiometry following the intracerebroventricular, intrathecal, and intraplantar application of low, systemically inactive doses of CRF. At each level, CRF elicits potent antinociceptive effects, which are dose dependent and antagonized by local, but not systemic CRF receptor antagonist alpha-helical CRF indicating CRF receptor specificity. Consistently, we have identified by immunohistochemistry multiple brain areas, inhibitory interneurons within the dorsal horn of the spinal cord as well as immune cells within subcutaneous tissue--but not peripheral sensory neurons--that coexpress both CRF receptors and opioid peptides. In line with these anatomical findings, local administration of CRF together with the opioid receptor antagonist naloxone dose-dependently reversed CRF's antinociceptive effects at each of these three levels of pain transmission. Therefore, local application of low, systemically inactive doses of CRF at the level of the brain, spinal cord and periphery inhibits tonic inflammatory pain most likely through an activation of CRF receptors on cells that coexpress opioid peptides which results in opioid-mediated pain inhibition. Future studies have to delineate whether endogenous CRF at these three levels contributes to the body's response to cope with the stressful stimulus pain in an opioid-mediated manner.
Mousa
Shaaban A
SA
Klinik für Anaesthesiologie und operative Intensivmedizin, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
Bopaiah
Cheppudira P
CP
Richter
Jan F
JF
Yamdeu
Reine S
RS
Schäfer
Michael
M
D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D005620:Freund's Adjuvant; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006727:Hormone Antagonists / Q000008:administration & dosage; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D008297:Male; D018847:Opioid Peptides / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D012584:Sciatic Nerve / Q000473:pathology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
D000700:Analgesics; D006727:Hormone Antagonists; D018847:Opioid Peptides; D018019:Receptors, Corticotropin-Releasing Hormone; C069206:alpha helical corticotropin-releasing hormone; D005620:Freund's Adjuvant; D003346:Corticotropin-Releasing Hormone