Vol. 299, Issue 3, 939-944, December 2001

2A-Adrenoceptor Stimulation Reduces Capsaicin-Induced Glutamate Release from Spinal Cord Synaptosomes

Xinhui Li and James C. Eisenach

Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Glutamate (Glu) is involved in excitatory neurotransmission and nociception and plays an essential role in relaying noxious stimuli in the spinal cord. Intrathecal or epidural injection of 2-adrenergic agonists produces potent antinociceptive effects, alters spinal neurotransmitter release, and effectively treats acute nociceptive and chronic neuropathic pain. Although it is generally believed that 2-adrenergic receptor stimulation reduces excitatory neurotransmitter release from peripheral afferents, the subtype of receptor causing this effect and its specificity to nociceptive neurotransmission have been inadequately studied. We therefore examined the pharmacology of adrenergic agents to inhibit Glu release in spinal cord from stimulation with capsaicin, a specific agonist for receptors on nociceptive afferents. Capsaicin evoked Glu release in synaptosomes from normal rat dorsal spinal cord in a concentration-dependent manner. Glu release from 30 µM capsaicin was inhibited by adrenergic agonists with a relative potency of clonidine = dexmedetomidine > norepinephrine > ST91 phenylephrine = 0, consistent with an action on 2A/D subtype receptors. Also consistent with this interpretation was the observation that inhibition of capsaicin-induced Glu release by clonidine or dexmedetomidine was blocked by the 2A/D antagonist BRL44408 but not by the 2B/C-preferring antagonist ARC239. Similar results were obtained in perfused spinal cord slices. These data suggest that capsaicin-evoked Glu release, likely reflecting stimulation of C fiber terminals, can be inhibited by activation of the 2A/D subtype, and this action of adrenergic agonists may reflect in part their efficacy in the treatment of acute pain.