In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 17, No. 18 ( 1997-09-15), p. 7157-7165
Abstract:
Agonists acting at α 2 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 α 2 agonist-evoked analgesia and adrenergic–opioid synergy. In the tail-flick test, intrathecal administration of UK 14,304, a nonsubtype-selective α 2 AR 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 α 2 -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 -ALA 2 , N -Me-Phe 4 ,Gly-ol 5 ]-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 α 2 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.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.17-18-07157.1997
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
1997
detail.hit.zdb_id:
1475274-8
SSG:
12
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