Do α2-adrenoceptors play an integral role in the antinociceptive mechanism of action of antidepressant compounds?

Gray, Alex M.; Pache, David; Sewell, Robert David Edmund

doi:10.1016/s0014-2999(99)00464-1

Cited by 99 publications

(62 citation statements)

References 39 publications

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“…Each SSRI drug may have a different mechanism of analgesic action. Among the possible mechanisms, opioidergic (11,12,15) and noradrenergic (12,16) mechanisms are listed in addition to serotonergic ones. In our study, paroxetine induced an antinociceptive effect starting approximately 60 min after injection and lasting for 60 min following i.p.…”

Section: Discussionmentioning

confidence: 99%

Possible Involvement of Opioidergic and Serotonergic Mechanisms in Antinociceptive Effect of Paroxetine in Acute Pain

et al. 2004

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Abstract. Antidepressant drugs, especially tricyclics have been widely used in the treatment of chronic pain, but not in acute pain. Because of numerous undesirable side effects, the selective serotonin reuptake inhibitors (SSRIs), with their favorable side effect profile, are preferred nowadays. An activation of the endogenous opioid mechanisms or potentiation of the analgesic effect mediated by serotonergic and / or noradrenergic pathways are thought to be involved in the antinociceptive action of SSRIs. In this study, the potential antinociceptive effect of paroxetine and its interaction with opioidergic system and serotonin receptors were evaluated. The antinociceptive effect of paroxetine was tested using a hot plate test in mice. Paroxetine, a SSRI antidepressant drug, induced an antinociceptive effect following i.p. administration. This antinociception was significantly inhibited by naloxone, an opioid receptor antagonist, suggesting the involvement of opioidergic mechanisms. While ondansetron (a 5-HT 3 -receptor antagonist) inhibited the effect of paroxetine, ketanserin (a 5-HT 2 -receptor antagonist) could not. In conclusion, paroxetine-induced antinociception, similar to morphine, suggests an involvement of direct or indirect action (via an increase in release of endogenous opioid peptide(s)) at opioid receptor sites and an involvement of serotonergic mechanisms mainly at the receptor level.

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Section: Discussionmentioning

confidence: 99%

Possible Involvement of Opioidergic and Serotonergic Mechanisms in Antinociceptive Effect of Paroxetine in Acute Pain

et al. 2004

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“…In humans, as well as in mice, treatment with tricyclic antidepressants (TCAs) produces mild analgesia (Ward et al, 1979;Tura and Tura, 1990;Gray et al, 1999). TCAs that block norepinephrine transporters (NETs), such as desipramine (DMI), prevent the presynaptic reuptake of norepinephrine (NE) and lead to increased postsynaptic NE levels.…”

Section: Abstract: Adrenergic; Monoamine Transporters; Opiates; Opiomentioning

confidence: 99%

“…Direct activation of ␣ 2 ARs has also been shown to potentiate morphine-induced spinal analgesia (Howe et al, 1983;Ossipov et al, 1990a,b;Roerig et al, 1992;Fairbanks and Wilcox, 1999). Interestingly, in addition to the mild analgesia reported after TCA treatment, a potentiation of opioid antinociception also occurs after coadministration of TCAs and morphine in both mice and humans (Kellstein et al, 1984(Kellstein et al, , 1988Hwang and Wilcox, 1987;Gray et al, 1998Gray et al, , 1999Reimann et al, 1999). Although the limited availability of pharmacologically selective ligands has prevented delineation of the particular ␣ 2 AR subtypes involved, many studies have implicated the ␣ 2A AR as the target for adrenergic antinociception (Millan et al, 1994;Graham et al, 1997).…”

Section: Abstract: Adrenergic; Monoamine Transporters; Opiates; Opiomentioning

confidence: 99%

Potentiated Opioid Analgesia in Norepinephrine Transporter Knock-Out Mice

et al. 2000

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Several studies have shown that activation of ␣ 2 -adrenergic receptors (␣ 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 ␣ 2 AR 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 tailflick assay, in NET-knock-out (-KO) mice than in wild-type (WT) mice. As anticipated, yohimbine, an inhibitor of ␣ 2 ARs, 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.

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“…[133] Topical Agents of the Modern Era: amitriptyline, clonidine and ketamine: Amitriptyline, a tricyclic antidepressant, has a number of actions including its ability to inhibit the reuptake of noradrenaline and serotonin. It has been shown to block various voltage gated ion channels including Na + , K + and Ca ++ [134,135] and several receptors including α2 adrenoceptor, cholinergic, NMDA and histamine [134][135][136] pointing to a use as a topical agent with peripheral nerve fibre effects. [137] Although not effective in every trial [138], amitriptyline at concentrations between 2-10%, along with some other antidepressant agents has been successfully used as a topical agent in a number of neuropathic pain states including complex regional pain syndrome (CRPS), multiple sclerosis and vulvodynia.…”

Section: Facit Ad Maximos Dolores -Useful For Extreme Painmentioning

confidence: 99%

Topical Treatment in Pain Medicine: From Ancient Remedies to Modern Usage

Finch¹,

Drummond

2015

Pain Manag.

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Abstract:Over several millennia, substances have been applied to the skin for treatment of pain. Some ingredients are in current use; others have been discontinued.Mechanisms of action include interactions with nociceptive neural networks and inflammatory processes. Substances must penetrate the stratum corneum barrier and vehicles that enhance penetration have been developed. Topical drugs with links to the past include menthol, capsaicin, some opioids, local anaesthetic agents and non-steroidal anti-inflammatory drugs. Mandragora is also described as an example of a herbal remedy that has been discontinued due to its toxicity. The future for topical drugs is promising, with the advent of new drugs tailored for specific pain mechanisms and the development of both penetration enhancers and sterile preparation methods.

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Do α2-adrenoceptors play an integral role in the antinociceptive mechanism of action of antidepressant compounds?

Cited by 99 publications

References 39 publications

Possible Involvement of Opioidergic and Serotonergic Mechanisms in Antinociceptive Effect of Paroxetine in Acute Pain

Possible Involvement of Opioidergic and Serotonergic Mechanisms in Antinociceptive Effect of Paroxetine in Acute Pain

Potentiated Opioid Analgesia in Norepinephrine Transporter Knock-Out Mice

Topical Treatment in Pain Medicine: From Ancient Remedies to Modern Usage

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