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

Abstract

The alpha 2A and alpha 2C adrenergic receptor (AR) subtypes mediate antinociception when activated by the endogenous 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 carrageenan/kaolin (3%) mixture did not differ among the experimental groups. However, the antihyperalgesia induced by both low and high frequency TENS was significantly diminished in alpha 2A mutant mice compared to controls. The alpha 2 adrenergic receptor selective antagonist, SK&F 86466, reversed TENS-mediated antihyperalgesia when delivered intra-articularly, but not when delivered intrathecally or intracerebroventricularly. These data suggest that peripheral alpha 2 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.