Endogenous opioid-mediated antinociception in cholestatic mice is peripherally, not centrally, mediated.
OBJECTIVE
Cholestasis is associated with naloxone reversible antinociception and opiate receptor antagonists are used clinically to treat pruritus. Pain and pruritus are closely interrelated and opioids modulate both sensations. Therefore, we undertook a series of experiments to characterize opioid-mediated antinociception in cholestasis and determine if it occurs inside or outside the CNS.


METHODS
Antinociception scores to both thermal and mechanical stimuli were determined in mice with cholestasis due to bile duct resection vs sham controls.


RESULTS
Cholestatic mice demonstrated significant antinociception to both stimuli compared to controls, which was reversible by the opiate receptor antagonist naloxone. The experiments were repeated with a naloxone derivative, which does not cross the blood-brain-barrier (i.e. naloxone methiodide) with similar results, indicating an opioid antinociceptive effect mediated outside of the CNS. Experiments with intraplantar injections of low dose naloxone methiodide confirmed that cholestasis-associated antinociception occurs at the level of cutaneous nerve endings. These findings were supported by findings of increased dermal met-enkephalin expression in cholestatic mice.


CONCLUSIONS
Cholestasis in mice is associated with antinociception due to local effects of endogenous opioids (i.e. met-enkephalin) at the level of sensory nerve endings. These findings may have direct implications in the management of cholestasis associated pruritus.
Nelson
Lisa
L
Liver Unit, Gastrointestinal Research Group, Health Sciences Center, University of Calgary, 3330 Hospital Dr., NW, Calgary, AB, Canada T2N 4N1.
Vergnolle
Nathalie
N
D'Mello
Charlotte
C
Chapman
Kevin
K
Le
Tai
T
Swain
Mark G
MG
D000818:Animals; D002779:Cholestasis / Q000150:complications / Q000503:physiopathology*; D004744:Enkephalin, Methionine / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018847:Opioid Peptides / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D017288:Pain Threshold; D011537:Pruritus / Q000209:etiology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000737:chemistry / Q000378:metabolism; D012867:Skin / Q000737:chemistry
D018847:Opioid Peptides; D012333:RNA, Messenger; D011957:Receptors, Opioid; D004744:Enkephalin, Methionine