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The Journal of Neuroscience, December 15, 2000, 20(24):9040-9045
Potentiated Opioid Analgesia in Norepinephrine Transporter
Knock-Out Mice
Laura M.
Bohn,
Fei
Xu,
Raul R.
Gainetdinov, and
Marc G.
Caron
Howard Hughes Medical Institute, Departments of Cell Biology and
Medicine, Duke University Medical Center, Durham, North Carolina 27710
Several studies have shown that activation of
 2-adrenergic receptors (2ARs) leads to
mild analgesic effects. Tricyclic antidepressants (TCAs), such as
desipramine (DMI), which block norepinephrine transporters (NETs), also
produce mild antinociception. The coadministration of either
2AR agonists or TCAs with opiates produces
synergistically potentiated antinociception. It has been postulated
that the analgesic effects of TCAs are determined by their ability to
inhibit norepinephrine reuptake via interactions with the NET. To test
this idea, we studied mice lacking a functional NET in spontaneous and
morphine-induced antinociceptive paradigms. Morphine (10 mg/kg, s.c.)
treatment produced greater analgesia, as assayed in the warm water
tail-flick assay, in NET-knock-out (-KO) mice than in wild-type (WT)
mice. As anticipated, yohimbine, an inhibitor of 2ARs,
blocked this potentiation. Moreover, a warm water swim-stress paradigm,
which is known to induce the release of endogenous opioids, produced greater antinociception in NET-KO than in the WT mice. Naloxone, an
inhibitor of opioid receptors, blocked the development of the swim-evoked analgesia in both WT and NET-KO mice, confirming the involvement of the endogenous opioid system. In the NET-KO mice, DMI
did not further enhance analgesia but was still able to produce inhibitory effects on the locomotor activity of these mutants, suggesting that the effects of this TCA are not exclusively via interactions with the NET. In summary, these results demonstrate in a
genetic model that both endogenous and exogenous opiate-mediated analgesia can be enhanced by elimination of the NET, indicating that
the interaction of TCAs with NET mediates these effects.
Key words:
adrenergic; monoamine transporters; opiates; opioid
receptors; antinociception; tricyclic antidepressants; desipramine
Copyright © 2000 Society for Neuroscience 0270-6474/00/20249040-06$05.00/0
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