Transcutaneous electrical nerve stimulation activates peripherally located alpha-2A adrenergic receptors

The alpha(2A) and alpha(2C) adrenergic receptor (AR) subtypes mediate antinociception when activated by the endogenousdog ligand norepinephrine. These receptors also produce antinociceptive synergy when activated concurrently with opioid receptor activation, The involvement of the opioid receptors in the mechanisms governing transcutaneous electrical nerve stimulation (TENS) has been well described. While spinal alpha-2 ARs do not appear to be involved in TENS antihyperalgesia in rats. the noradrenergic analgesic system also involves supraspinal and peripheral sites. Thus, a broader evaluation of the potential contribution of alpha-2 AR to TENS is warranted, The current study compared the antihyperalgesic efficacy of high (100 Hz) and low (4 Hz) frequency TENS in mutant mice lacking a functional alpha(2A) AR against their respective wildtype counterparts. The degree of secondary heat hyperalgesia induced by intra-articular injection of carrageenatt/kaolin (3%) mixture did not differ among the experimental groups. However, the antihypcralgesia induced by both low and high frequency TENS was significantly diminished in alpha(2A) mutant m ice compared to controls. The alpha, adrenergic receptor selective antagonist, SK&F86460. reversed-TENS-mediated antihyperalgesia when delivered intra-articularly, but not when delivered intrathecally or intracerebrmentricularly, These data suggest that peripheral alpha(2A) ARs contribute, in part. to TENS antihyperalgesia. This pharmacodynamic response is consistent with previous anatomical observations that alpha(2A) ARs are expressed on primary afferent neurons and macrophages near injured tissue. (c) 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.