Potentiated opioid analgesia in norepinephrine transporter knock-out mice

Several studies have shown that activation of alpha (2)-adrenergic receptor s (alpha (2)ARs) 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 alpha (2)AR agonists or TCAs with opiates produces synergistically potentia ted antinociception. It has been postulated that the analgesic effects of T CAs are determined by their ability to inhibit norepinephrine reuptake via interactions with the NET. To test this idea, we studied mice lacking a fun ctional 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 wil d-type (WT) mice. As anticipated, yohimbine, an inhibitor of alpha (2)ARs, blocked this potentiation. Moreover, a warm water swim-stress paradigm, whi ch is known to induce the release of endogenous opioids, produced greater a ntinociception in NET-KO than in the WT mice. Naloxone, an inhibitor of opi oid receptors, blocked the development of the swim-evoked analgesia in both WT and NET-KO mice, confirming the involvement of the endogenous opioid sy stem. In the NET-KO mice, DMI did not further enhance analgesia but was sti ll able to produce inhibitory effects on the locomotor activity of these mu tants, suggesting that the effects of this TCA are not exclusively via inte ractions with the NET. In summary, these results demonstrate in a genetic m odel that both endogenous and exogenous opiate-mediated analgesia can be en hanced by elimination of the NET, indicating that the interaction of TCAs w ith NET mediates these effects.