The α(2a) adrenergic receptor subtype mediates spinal analgesia evoked by α2 agonists and is necessary for spinal adrenergic-opioid synergy

Laura S. Stone, Leigh B. MacMillan, Kelley F. Kitto, Lee E. Limbird, George L. Wilcox

Research output: Contribution to journalArticlepeer-review

213 Scopus citations

Abstract

Agonists acting at α2 adrenergic and opioid receptors have analgesic properties and act synergistically when co-administered in the spinal cord; this synergy may also contribute to the potency and efficacy of spinally administered morphine. The lack of subtype-selective pharmacological agents has previously impeded the definition of the adrenergic receptor subtype(s) mediating these effects. We therefore exploited a genetically modified mouse line expressing a point mutation (D79N) in the α(2a) adrenergic receptor (α(2a)AR) to investigate the role of the α(2a)AR in α2 agonist-evoked analgesia and adrenergic-opioid synergy. In the tail-flick test, intrathecal administration of UK 14,304, a nonsubtype-selective α2AR agonist, had no analgesic effect in D79N mice, whereas the analgesic potency of morphine (intrathecal) in this assay was not affected by the mutation. The mutation also decreased α2-agonist-mediated spinal analgesia and blocked the synergy seen in wild-type mice with both the δ-opioid agonist deltorphin II and the μ-opioid agonist [D-ALA2,N-Me-Phe4,Gly-ol5]-Enkephalin (DAMGO) in the substance P behavioral test. In addition, the potency of spinally administered morphine was decreased in this test, suggesting that activation of descending noradrenergic systems impinging on the α(2a)AR contributes to morphine-induced spinal inhibition in this model. These results demonstrate that the α(2a)AR subtype is the primary mediator of α2 adrenergic spinal analgesia and is necessary for analgesic synergy with opioids. Thus, combination therapies targeting the α(2a)AR and opioid receptors may prove useful in maximizing the analgesic efficacy of opioids while decreasing total dose requirements.

Original languageEnglish (US)
Pages (from-to)7157-7165
Number of pages9
JournalJournal of Neuroscience
Volume17
Issue number18
DOIs
StatePublished - 1997

Keywords

  • Antinociception
  • Gene targeting
  • Intrathecal
  • Isobologram
  • Mice
  • Morphine
  • Opioid
  • Substance P
  • Synergy
  • α adrenergic receptor
  • α(2a)AR

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