title: Transcutaneous electrical nerve stimulation activates peripherally located alpha-2A adrenergic receptors.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, USA Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA Center for Pain Research, University of Minnesota, Minneapolis, MN 55455, USA Graduate Program in Physical Therapy and Rehabilitation Science Graduate Program, University of Iowa, Iowa City, IA 52242-1190, USA Graduate Program in Neuroscience Graduate Program, University of Iowa, Iowa City, IA 52242-1190, USA Graduate Program in Pain Research Program, University of Iowa, Iowa City, IA 52242-1190, USA Graduate Program in College of Medicine, University of Iowa, Iowa City, IA 52242-1190, USA.
authors.forename: Ellen W
authors.initials: EW
authors.lastname: King
authors.forename: Katherine
authors.initials: K
authors.lastname: Audette
authors.forename: Gwendolyn A
authors.initials: GA
authors.lastname: Athman
authors.forename: Oanh X H
authors.initials: OXH
authors.lastname: Nguyen
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Sluka
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Fairbanks
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002351:Carrageenan; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology* / Q000628:therapy*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009475:Neurons, Afferent / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000502:physiology; D004561:Transcutaneous Electric Nerve Stimulation
chemical_list: C547769:Adra2a protein, mouse; D000317:Adrenergic alpha-Antagonists; D001552:Benzazepines; D018341:Receptors, Adrenergic, alpha-2; D002351:Carrageenan; C039139:benalfocin