Spinal 5-HT7 Receptors Play an Important Role in the Antinociceptive and Antihyperalgesic Effects of Tramadol and Its Metabolite, O-Desmethyltramadol, via  Activation of Descending Serotonergic Pathways

Yanarateş, Ömer; Doğrul, Ahmet; Yıldırım, Vedat; Şahin, Altan; Sızlan, Ali; Seyrek, Melik; Akgül, Özgür; Kozak, Orhan; Kurt, Ercan; Aypar, Ülkü

doi:10.1097/aln.0b013e3181cd7920

Cited by 81 publications

(53 citation statements)

References 53 publications

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“…It has already been demonstrated that tramadol has less affinity for the l-opioid receptor than morphine and only 40% antinociception of tramadol was antagonized by naloxone [2], indicating that another non-opioid mechanism might contribute to the overall analgesic effect of tramadol. Moreover, it has been reported that the antinociceptive effect of tramadol was significantly diminished in 5-HT-lesioned mice, and intrathecal injection of 5-HT receptor antagonists blocked tramadol-induced antinociception, indicating that the descending serotonergic pathways and spinal 5-HT receptors are of crucial importance in the antinociceptive effects of tramadol [18]. These findings, together with our results, suggest that the dual mechanisms proposed in previous studies [2][3][4][5] may be relevant to the antinociception of tramadol at the spinal level, and a 2 -adrenoceptors may be important in modulation of the antinociception of tramadol at the spinal level.…”

Section: Discussionmentioning

confidence: 98%

The antinociceptive effect of intrathecal tramadol in rats: the role of alpha 2-adrenoceptors in the spinal cord

Chen²,

Chen³

et al. 2011

J Anesth

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Section: Discussionmentioning

confidence: 98%

The antinociceptive effect of intrathecal tramadol in rats: the role of alpha 2-adrenoceptors in the spinal cord

Chen²,

Chen³

et al. 2011

J Anesth

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“…Also, the antinociceptive effect of tramadol was significantly diminished in 5-HT-lesioned mice. Previous data suggested that the descending serotonergic pathways and spinal 5-HT receptors play a crucial role in the antinociceptive and antihyperalgesic effects of tramadol [38,39]. On the other hand, another recent study observed that the intrathecal injection of minocycline significantly attenuated mechanical allodynia in a rat SNL model [40].…”

Section: Discussionmentioning

confidence: 99%

Depressing Interleukin-1� Contributed to the Synergistic Effects of Tramadol and Minocycline on Spinal Nerve Ligation-Induced Neuropathic Pain

Mei

Sakuma²,

Xie

et al. 2014

Neurosignals

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Our previous study indicated that coadministration of tramadol and minocycline exerted synergistic effects on spinal nerve ligation (SNL)-induced neuropathic mechanical allodynia. However, the underlying mechanisms are still unclear. Recent reports indicated that spinal proinflammatory factor interleukin-1β (IL-1β) contributed to the development of neuropathic pain and the positive feedback communication between neuron and glia. Therefore, the present research is to confirm whether spinal IL-1β-related pathway response contributes to the synergistic effects of tramadol and minocycline on SNL-induced neuropathic pain. Real-time RT-PCR demonstrated IL-1β up-expression in the ipsilateral spinal dorsal horn 3 days after lesion, which could be significantly decreased by tramadol and minocycline coadministration. Immunofluorescence and Western blot indicated that SNL-induced microglial phosphorylated p38 (p-p38) upregulation was also inhibited by tramadol and minocycline coapplication. Meanwhile, intrathecal administration of p38 inhibitor SB203580 markedly alleviated mechanical allodynia whilst reducing IL-1β and Fos expression induced by SNL. Moreover, intrathecal neutralized antibody of IL-1β could depress SNL-induced mechanical allodynia and Fos expression. These results suggest that depressing SNL-induced aberrant activation of the spinal dorsal horn IL-1β-related pathway contributes to the underlying mechanism of the synergistic effects of tramadol and minocycline coadministration on SNL-induced neuropathic mechanical allodynia. © 2013 S. Karger AG, Basel

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“…Similarly, intrathecal injection of the 5-HT 7 receptor antagonists SB-269970 and SB-258719 has been recently shown to block the antinociceptive and antihyperalgesic effects of both tramadol and its opioid metabolite M1 (3). Accordingly, both tramadol-and M1-induced antinociceptive effects were found to be significantly diminished in 5-HT lesioned mice (3). Because selective 5-HT 7 receptor antagonists reversed the antinociceptive effects of morphine, it can be hypothesized that activation of 5-HT 7 receptors might enhance morphine-induced antinociception.…”

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confidence: 94%

Potentiation of Morphine Analgesia by Adjuvant Activation of 5-HT7 Receptors

et al. 2011

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Abstract. Spinal blockade of 5-HT 7 receptors has been reported to inhibit the antinociceptive effect of opioids. In this study, we found that subcutaneous administration of the selective 5-HT 7 receptor agonist E-55888 (10 mg/kg) or the antagonist SB-258719 (5 mg/kg) exerted no effect on the tail-flick test in mice. However, E-55888, but not SB-258719, increased (2.6-fold) the analgesic potency of oral morphine. The potentiating effect exerted by E-55888 was prevented by SB-258719. A pharmacokinetic interaction was discarded as morphine plasma and brain concentrations were not significantly modified when co-administered with E-55888. These results reinforce the involvement of 5-HT 7 receptors in opioid analgesia and point to a potential use of 5-HT 7 receptor agonists as adjuvants of opioid analgesia.

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Spinal 5-HT7 Receptors Play an Important Role in the Antinociceptive and Antihyperalgesic Effects of Tramadol and Its Metabolite, O-Desmethyltramadol, via Activation of Descending Serotonergic Pathways

Abstract: These findings suggest that the descending serotonergic pathways and spinal 5-HT7 receptors play a crucial role in the antinociceptive and antihyperalgesic effects of tramadol and M1.

Cited by 81 publications

References 53 publications

The antinociceptive effect of intrathecal tramadol in rats: the role of alpha 2-adrenoceptors in the spinal cord

The antinociceptive effect of intrathecal tramadol in rats: the role of alpha 2-adrenoceptors in the spinal cord

Depressing Interleukin-1� Contributed to the Synergistic Effects of Tramadol and Minocycline on Spinal Nerve Ligation-Induced Neuropathic Pain

Potentiation of Morphine Analgesia by Adjuvant Activation of 5-HT7 Receptors

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