Pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine1A/1B antagonist, enhances the analgesic effect of tramadol

Abstract

The ability of pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine(1A/1B) antagonist, to enhance the clinical antidepressant response to selective serotonin re-uptake inhibitors is generally attributed to a blocking of the feedback that inhibits the serotoninergic neuronal activity mediated by somatodendritic 5-hydroxytryptamine (5-HT)(1A) autoreceptors. The current study examined the ability of pindolol to enhance the analgesic effect of tramadol, an atypical centrally-acting analgesic agent with relatively weak opioid receptor affinity and which, like some antidepressants, is able to inhibit the re-uptake of 5-HT in the raphe nuclei. Racemic pindolol (2 mg/kg, s.c.), rendered analgesic a non-effective acute dose of tramadol (10-40 mg/kg, i.p.) in two nociceptive tests: a hot plate test in mice and a plantar test in rats. Moreover, (+/-)8-OH-DPAT (0.125-1 mg/kg, s.c.), a selective 5-HT(1A) agonist, reduces the analgesic effect of tramadol in the same tests. These results suggest an implication of the somatodendritic 5-HT(1A) receptors in the analgesic effect of tramadol and open a new adjuvant analgesic strategy for the use of this compound.

Role of serotonin 5-HT1A and opioid receptors in the antiallodynic effect of tramadol in the chronic constriction injury model of neuropathic pain in rats

“…This study confirms our results from previous studies with acute models of pain, the hot-plate test in mice and plantar test in rats Rojas-Corrales et al 2000) and contributes to support the evidence in favour of the role of the serotoninergic system in the analgesic effect of tramadol in healthy and mononeuropathic subjects. On serotonergic perikarya in the nucleus raphe magnus and other serotonergic nuclei, inhibitory 5-HT 1A autoreceptors exert a pronounced inhibitory influence upon the release of 5-HT throughout the CNS.…”

“…We have previously reported that the antinociceptive effect of tramadol is enhanced in acute pain models by the systemic administration of both pindolol, a putative antagonist of β-adrenergic and 5-HT 1A/B receptors (Rojas-Corrales et al 2000), and WAY-100635, a selective antagonist of 5-HT 1A receptors, and reduced by the selective agonist of 5-HT 1A receptors, 8-OH-DPAT, systemically injected Rojas-Corrales et al 2000. Therefore, considering that cold allodynia is one of the main clinical symptoms of neuropathic pain (Zimmermann 2001), the present study was designed to examine the role of 5-HT 1A receptors and opioid receptors in the cold-antiallodynic effects of tramadol in sciatic nerve-ligated rats, trying to elucidate the cooperative or non-cooperative role of 5-HT 1A and opioid receptors in tramadol antinociception.…”

CYP2D6 in the Metabolism of Opioids for Mild to Moderate Pain

“…However, tramadol administered alone does not influence the possibility of fits [41] . In rats and mice, concomitant administration of tramadol and pindolol, a ␤ -blocker and 5HT1A/1B antagonist, enhances analgesia [42] . According to Sindrup et al [43] , the opioid effect of (+)-M 1 may be of importance for tramadol-induced relief of ongoing neuropathic pain but, in general, relief of neuropathic pain seems to depend on both the monoaminergic effect of (+)-and (-)-tramadol and the opioid effect of (+)-M 1 [43] .…”

Synergistic interaction between tramadol and dipyrone in thermal paw stimulation model in the rat

“…It has been suggested that opioid and non-opioid mechanisms may be involved in such potentiation [Satvanaravana et al, 2004]. Another mechanism that has been suggested is that of the somatodendritic 5-HT 1A receptors [Rojas-Corrales et al, 2000]. On the other hand, in order to obtain a synergistic interaction, metamizol has been also combined with different analgesics or analgesic adjuvants including morphine [Hernández-Delgadillo et al, 2002], gabapentin [Ortega-Varela et al, 2007], and caffeine [Díazaz-Reval et al, 2008].…”