Intrathecal adenosine interacts with a spinal noradrenergic system to produce antinociception in nerve-injured rats.
BACKGROUND
Adenosine analogs produce antinociception in animal models of acute pain, reduce hypersensitivity in models of inflammatory and nerve-injury pain, and stimulate neurotransmitter release in the brain. Adenosine itself is entering clinical trials for analgesia, and the current study examined the effect, mechanisms of action, and interaction with noradrenergic systems of intrathecal adenosine in a rat model of neuropathic pain.


METHODS
The left L5 and L6 spinal nerve roots were ligated and, 1 week later, an intrathecal catheter was inserted in male rats. Withdrawal threshold to mechanical stimulation of the left hind paw was determined before and after surgery, confirming mechanical hypersensitivity. The effects of intrathecal adenosine, clonidine, and their combination on withdrawal threshold were determined, and reversal of the effects of adenosine by adenosine and alpha2-adrenergic antagonists and by destruction of noradrenergic nerve terminals was tested. Finally, spinal cord slices were perfused in vitro with the adenosine agonist 5'-N-ethylcarboxamide adenosine, and norepinephrine release was measured.


RESULTS
Intrathecal adenosine and clonidine reduced hypersensitivity and interacted in an additive manner. The effects of adenosine were blocked by intrathecal injection of A1 but not A2 adenosine receptor antagonists, by an alpha2-adrenergic antagonist, and by destruction of spinal noradrenergic nerve terminals. Perfusion of spinal cord slices with 5'-N-ethylcarboxamide adenosine resulted in a concentration-dependent increase in norepinephrine release.


CONCLUSIONS
These data support clinical examination of intrathecal adenosine alone and with clonidine in the treatment of chronic pain states that include a component of mechanical hypersensitivity and suggest that, after nerve injury, adenosine acts to reduce hypersensitivity through spinal norepinephrine release.
Gomes
J A
JA
Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1009, USA.
Li
X
X
Pan
H L
HL
Eisenach
J C
JC
D000241:Adenosine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007278:Injections, Spinal; D008026:Ligation; D008297:Male; D009619:Nociceptors / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism / Q000502:physiology*; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects; D013126:Spinal Nerve Roots / Q000502:physiology* / Q000601:surgery
D000700:Analgesics; D018047:Receptors, Purinergic P1; D000241:Adenosine; D009638:Norepinephrine