Exogenous and endogenous adenosine enhance the spinal antiallodynic effects of morphine in a rat model of neuropathic pain.
Adenosine analogs produce antinociception in normal animals and reduce allodynia and hyperalgesia following inflammation and nerve injury following spinal injection, yet none have been tested for clinical safety. While adenosine itself is in clinical trials for spinal administration, there is little data on the spinal effects of adenosine in animal models. In this study, we determined that the spinal administration of adenosine produced a dose-dependent reduction in tactile allodynia in rats following spinal nerve ligation without producing motor blockade. Although the maximal effect of adenosine was less than 50% reversal of allodynia, its duration of action was >24 h after a single spinal injection. In contrast, injection of a synthetic adenosine analog which produced an anti-allodynic action to a similar degree of effect resulted in a pronounced motor blockade. Spinal opioid action has been suggested to result in part from spinal adenosine release. We hypothesized that the reduced efficacy of spinal morphine in nerve injury-induced allodynia and hyperalgesia might reflect a disruption in this spinal opioid-adenosine mechanism. Spinal morphine itself produced a minimal reduction in allodynia in rats following spinal nerve ligation and this was enhanced in an additive manner by spinal adenosine. The maximal effect of this combination resulted in less than 60% reversal of allodynia. In contrast, spinal injection of adenosine deaminase or reuptake inhibitors greatly enhanced the effect of spinal morphine, resulting in over 80% reversal of allodynia. These results support the clinical testing of spinal adenosine alone and with morphine in the treatment of neuropathic pain, and further testing of the proposed opioid-adenosine link in normal and hyperesthetic conditions.
Lavand'homme
P M
PM
Department of Anesthesiology, Université Catholique de Louvain, Brussels, Belgium.
Eisenach
J C
JC
D000241:Adenosine / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D003839:Deoxyadenosines / Q000494:pharmacology; D004176:Dipyridamole / Q000494:pharmacology; D004357:Drug Synergism; D007278:Injections, Spinal; D008026:Ligation; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000627:therapeutic use*; D009443:Neuritis / Q000503:physiopathology; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D010147:Pain Measurement; D010812:Physical Stimulation; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves
D000701:Analgesics, Opioid; D003839:Deoxyadenosines; D058906:Purinergic P1 Receptor Agonists; C057928:5'-amino-5'-deoxyadenosine; D004176:Dipyridamole; D009020:Morphine; D000241:Adenosine