Morphine-induced spinal release of adenosine is reduced in neuropathic rats.
BACKGROUND
Spinally administered opioids show decreased potency and efficacy in the treatment of neuropathic pain. As reported previously, morphine stimulates spinal opioid receptors to effect adenosine release, which acts at adenosine receptors to produce analgesia. The authors hypothesized that morphine induces less adenosine release in neuropathic compared with normal rats, explaining its reduced potency and efficacy.


METHODS
Sprague-Dawley rats (200-250 g) were divided into three groups: no surgery (n = 52), sham surgery (n = 20), or left L5 and L6 spinal nerve ligation (n = 64). Two weeks after surgery, mechanical hypersensitivity of the left hind paw was verified. For each experiment, a crude synaptosomal P2 suspension was prepared by homogenizing cervical and lumbar dorsal spinal cord halves from four rats, followed by differential centrifugation, and aliquots incubated with morphine sulfate from 10(-8) to 10(-4) m alone or in presence of 10(-5) m dipyridamole. Extrasynaptosomal concentrations of adenosine were analyzed by high-pressure liquid chromatography.


RESULTS
Synaptosomal release of adenosine in the absence of morphine was similar between groups. Morphine produced a concentration-dependent adenosine release, which was less in synaptosomes from dorsal lumbar spinal cord in spinal nerve ligation compared with normal or sham animals. This reduction was removed by adding dipyridamole.


CONCLUSIONS
Morphine normally stimulates spinal release of adenosine, a potent antihypersensitivity compound. Because this effect of morphine is diminished in spinal nerve ligation animals, one explanation for decreased efficacy and potency of opioids in the treatment of neuropathic pain may be a dipyridamole-sensitive disruption in the opioid-adenosine link in the spinal cord.
Sandner-Kiesling
A
A
Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1009, USA.
Li
X
X
Eisenach
J C
JC
D000241:Adenosine / Q000378:metabolism*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004176:Dipyridamole / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D010523:Peripheral Nervous System Diseases / Q000378:metabolism*; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013127:Spinal Nerves / Q000187:drug effects / Q000293:injuries; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D000701:Analgesics, Opioid; D014665:Vasodilator Agents; D004176:Dipyridamole; D009020:Morphine; D000241:Adenosine