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Volume 17, Number 18,
Issue of September 15, 1997
pp. 7157-7165
Copyright ©1997 Society for Neuroscience
The  2a Adrenergic Receptor Subtype Mediates Spinal
Analgesia Evoked by 2 Agonists and Is Necessary for
Spinal Adrenergic-Opioid Synergy
Received April 18, 1997; revised June 25, 1997; accepted July 8, 1997.
Laura S. Stone1, 2,
Leigh B. MacMillan3,
Kelley
F. Kitto2,
Lee E. Limbird3, and
George L. Wilcox1, 2
1 Graduate Program in Neuroscience and
2 Department of Pharmacology, University of Minnesota,
Minneapolis, Minnesota 55455, and 3 Department of
Pharmacology, Vanderbilt University, Nashville, Tennessee 37232
Agonists acting at  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 2a adrenergic
receptor (2aAR) to investigate the role of the
2aAR in 2 agonist-evoked analgesia and
adrenergic-opioid synergy. In the tail-flick test, intrathecal administration of UK 14,304, a nonsubtype-selective 2AR
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
2-agonist-mediated spinal analgesia and blocked the
synergy seen in wild-type mice with both the  -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
2aAR contributes to morphine-induced spinal inhibition
in this model. These results demonstrate that the 2aAR
subtype is the primary mediator of 2 adrenergic spinal
analgesia and is necessary for analgesic synergy with opioids. Thus,
combination therapies targeting the 2aAR and opioid
receptors may prove useful in maximizing the analgesic efficacy of
opioids while decreasing total dose requirements.
Key words:
2 adrenergic receptor;
synergy;
mice;
morphine;
antinociception;
intrathecal;
substance P;
opioid;
isobologram;
gene targeting;
2aAR
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