title: The alpha(2A) adrenoceptor and the sympathetic postganglionic neuron contribute to the development of neuropathic heat hyperalgesia in mice.
abstract: We have addressed the role of the sympathetic nervous system in the development and maintenance of neuropathic pain. Using a new neuropathic mouse model, we examined the development of hyperalgesia in transgenic mice lacking functional alpha(2A) adrenoceptors and in sympathectomized wild-type mice, to determine if sympathetic-sensory coupling generates hyperalgesia. The development of neuropathic heat hyperalgesia required the presence of both the alpha(2A) adrenoceptor and the sympathetic postganglionic neuron (SPGN), but the development of mechanical hyperalgesia did not require either the alpha(2A) adrenoceptor or the SPGN, indicating different mechanisms of sensitization. These results suggest that the development of neuropathic heat hyperalgesia, but not mechanical hyperalgesia, requires sympathetic-sensory coupling in the peripheral nervous system. Nerve injury enhanced the analgesic efficacy of the alpha(2) adrenoceptor agonist dexmedetomidine, and paradoxically also induced an analgesic response to alpha(2) adrenoceptor antagonists. The alpha(2) agonist-evoked analgesia to mechanical stimuli was mediated by activating central alpha(2A) adrenoceptors, possibly at the spinal level. The peripherally restricted alpha(2) antagonist L659,066 evoked analgesia for heat, but not for mechanical stimuli, findings which support the hypothesis that the peripheral alpha(2) adrenoceptor plays a role in both the development and the maintenance of neuropathic heat hyperalgesia. The alpha(2) antagonist-evoked analgesia for heat stimuli was mediated by blocking peripheral and probably central alpha(2) adrenoceptors, while the analgesia for mechanical stimuli was mediated by blocking central alpha(2A) adrenoceptors. Intradermal injections with an alpha(2) agonist or antagonist had no effect on nociceptive thresholds, indicating that sympathetic-sensory coupling at the level of the cutaneous nociceptor did not contribute to the maintenance of neuropathic hyperalgesia.
authors.affiliation: Department of Functional Restoration, Stanford University, Stanford, CA, USA Department of Physical Medicine and Rehabilitation, Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA Department of Anesthesia, Stanford University, Stanford, CA, USA Department of Anesthesiology Services, Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Wade S
authors.initials: WS
authors.lastname: Kingery
authors.forename: Tian Z
authors.initials: TZ
authors.lastname: Guo
authors.forename: Frances M
authors.initials: FM
authors.lastname: Davies
authors.forename: Lee
authors.initials: L
authors.lastname: Limbird
authors.forename: Mervyn
authors.initials: M
authors.lastname: Maze
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D020927:Dexmedetomidine / Q000494:pharmacology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology*; D007530:Isoflurane / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D009619:Nociceptors / Q000502:physiology; D010147:Pain Measurement; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000378:metabolism; D010812:Physical Stimulation; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism / Q000502:physiology*; D013562:Sympathectomy; D017779:Sympathetic Fibers, Postganglionic / Q000378:metabolism / Q000502:physiology*; D013979:Tibial Nerve / Q000293:injuries / Q000378:metabolism
chemical_list: C547769:Adra2a protein, mouse; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018712:Analgesics, Non-Narcotic; D018685:Anesthetics, Inhalation; D018341:Receptors, Adrenergic, alpha-2; D020927:Dexmedetomidine; D007530:Isoflurane