The alpha2A and alpha2C 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 alpha2A 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 alpha2A mutant mice compared to controls. The alpha2 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 alpha2 ARs contribute, in part, to TENS antihyperalgesia. This pharmacodynamic response is consistent with previous anatomical observations that alpha2A ARs are expressed on primary afferent neurons and macrophages near injured tissue.
Bibliographical noteFunding Information:
We extend our great appreciation to Dr George Wilcox for support of the mouse colonies, to Dr Paul Hieble for generous donation of the SK&F 86466 compound, to Dr Laura S. Stone for valuable critique of this manuscript, and to Mr Kelley F. Kitto and Ms H. Yen X. Nguyen for excellent technical assistance. This work was supported by NIDA research grants DA-00509 (CAF), DA015735 (CAF), and by the Melendy Research Fellowship Program of the University of Minnesota College of Pharmacy (GAA), the Arthritis Foundation (KAS), K02 AR02201 (KAS), and the Carver College of Medicine, University of Iowa (EWK). TENS units were donated by EMPI, Inc., Minneapolis, MN.
- Spinal cord