Spinal noradrenergic activation mediates allodynia reduction from an allosteric adenosine modulator in a rat model of neuropathic pain

Activation of adenosine Al receptors by endogenous adenosine or synthetic agonists produces anti-nociception in animal models of acute pain and also reduces hypersensitivity in models of inflammatory and nerve-injury pain, Allosteric adenosine modulators facilitate adenosine agonist binding to the Al receptor. The purpose of the current study was to examine the effect, mechanisms of action, and interaction with noradrenergic systems of intrathecal (i.t.) or oral administration of the allosteric adenosine modulator T62 in a rat model of neuropathic pain. A spinal nerve ligation rat model (SNL; ligation of left L5 and L6 spinal nerve roots) was used. One week after SNL surgery, an i.t. catheter was inserted. Withdrawal threshold to mechanical stimulation of the left hind paw was determined before and after surgery, confirming mechanical hypersensitivity. Oral or i.t. T62 reduced hypersensitivity induced by SNL. The effects of i.t. T62 were inhibited by i.t. injection of an A I receptor antagonist and by an alpha2-adrenergic antagonist but not by an A2 adenosine receptor antagonist. Anti-dopamine beta hydroxylase (DbetaH)-saporin treatment reduce spinal norepinephrine content by 97%, accompanied by an almost complete loss of DbetaH immunoreactive axons in the spinal dorsal horn and neurons in the locus coeruleus. The effect of T62 was completely lost in animals treated with anti-DbetaH-saporin. These data support the hypothesis that activation of the Al receptor by the allosteric modulator, T62, produces anti-nociception via spinal noradrenergic activation. (C) 2002 Published by Elsevier Science B.V. on behalf of International Association for the Study of Pain.