Differential mediation of descending pain facilitation and inhibition by spinal 5HT-3 and 5HT-7 receptors

Gulhane Military Academy of Medicine, Department of Pharmacology, Ankara, Turkiye.
Brain research (Impact Factor: 2.84). 06/2009; 1280:52-9. DOI: 10.1016/j.brainres.2009.05.001
Source: PubMed


The rostroventromedial medulla (RVM) is an important source of descending modulatory systems that both inhibit and facilitate pain at the level of the spinal cord. Noxious stimuli can activate serotonergic neurons in the RVM and accelerate the turnover of 5-HT in the spinal cord. While numerous studies suggest a bidirectional role for serotonergic transmission at the spinal level, the subtypes of the 5-HT receptors that are associated with descending facilitation or inhibition have not been clearly determined. Here, we explore the relative contribution of spinal 5-HT7 and 5-HT3 receptors to antinociception or hyperalgesia associated with states of enhanced net descending inhibition or facilitation from the RVM. In uninjured rats, RVM microinjection of morphine produced dose-dependent antinociception in the noxious thermal paw flick test while RVM microinjection of CCK produced thermal hyperalgesia and tactile allodynia. Spinal administration of the 5-HT7 antagonist SB-269970, but not of the 5-HT3 antagonist ondansetron, blocked the antinociceptive effects of RVM morphine. In contrast, hyperalgesia induced by RVM-CCK was blocked by spinal ondansetron, but not by SB-269970. The antinociceptive effects of systemic morphine were also blocked by spinal SB-269970 but not ondansetron while hyperalgesia and allodynia resulting from SNL injury were blocked by spinal ondansetron, but not SB-269970. These studies suggest that descending pain inhibitory or facilitatory pathways from RVM act ultimately in the spinal cord in acute and chronic pain states through activation of 5-HT7 and 5-HT3 receptors, respectively.

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    • "Consistent with these views and a recent study [50], our data showed that blockade of spinal 5-HT3 receptor function by intrathecal Y25130, a selective 5-HT3 receptor antagonist, attenuated mechanical and thermal hypersensitivity following L5 SNL in rats. Interestingly, some studies reported that intrathecal injection of 5-HT3 receptor antagonists such as CGP35348 [51] or ondansetron [52] had no preventive effects on mechanical allodynia and/or thermal hyperalgesia in a rat with L5/6 SNL, which conflicts with the study with the same drug ondansetron in the same SNL model [50] and our results. However, we noticed that there were no expected plastic changes of both 5-HT immunoreactive intensity and 5-HT3 receptor innervation in the lumbar spinal dorsal horn at 14 d after L5/L6 SNL in the study reported by Peters and colleagues [52]. "
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    ABSTRACT: Background It has been recently recognized that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in the brainstem and the 5-HT3 receptor subtype in the spinal dorsal horn are involved in enhanced descending pain facilitation after tissue and nerve injury. However, the mechanisms underlying the activation of the 5-HT3 receptor and its contribution to facilitation of pain remain unclear. Results In the present study, activation of spinal 5-HT3 receptors by intrathecal injection of a selective 5-HT3 receptor agonist SR 57227 induced spinal glial hyperactivity, neuronal hyperexcitability and pain hypersensitivity in rats. We found that there was neuron-to-microglia signaling via the chemokine fractalkine, microglia to astrocyte signaling via cytokine IL-18, astrocyte to neuronal signaling by IL-1β, and enhanced activation of NMDA receptors in the spinal dorsal horn. Glial hyperactivation in spinal dorsal horn after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference. Conclusions These findings offer new insights into the cellular and molecular mechanisms at the spinal level responsible for descending 5-HT-mediated pain facilitation during the development of persistent pain after tissue and nerve injury. New pain therapies should focus on prime targets of descending facilitation-induced glial involvement, and in particular the blocking of intercellular signaling transduction between neurons and glia.
    Molecular Pain 06/2014; 10(1):35. DOI:10.1186/1744-8069-10-35 · 3.65 Impact Factor
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    • "Other studies partially contradict above listed studies. Through activation of 5-HT-3-Rs, central serotonergic circuits can modulate nociceptive transmission via a facilitatory pathways in the spinal cord (Zeitz et al., 2002; Dogrul et al., 2009). Intrathecal injection of 5-HT-3-R antagonists reduce nociceptive responses to noxious heat in rats (Ali et al., 1996). "
    W Mei · M Li · Y Yu · C.W. Cheung · F Cao · B Nie · Z Zhang · P Wang · Y Tian ·
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    ABSTRACT: Studies have suggested that 5-hydroxytryptamine-3A (5-HT-3A) receptor antagonists may have analgesic effects. This randomized, double-blind, placebo-controlled, factorial study tested the hypothesis that 5-HT-3A receptor antagonist tropisetron attenuates post-operative pain in women receiving either sevoflurane or propofol based anaesthesia. Two hundred and ninety-six women undergoing gynaecological laparoscopies were randomly assigned to be anaesthetized with either sevoflurane or propofol. Immediately after the induction of anaesthesia, the anaesthesiologist administered either tropisetron 2 mg or a placebo intravenously. Pain score at rest at 0.5 h post-operatively reported using a numerical rating scale was the primary outcome measure. The secondary outcome measures included pain score at rest every 2 h within the first 24 h post-operatively, duration of post-anaesthesia care unit stay, incidence of post-operative nausea and vomiting, the incidence of shivering and score of the Quality of Recovery Score 40. Compared with placebo, tropisetron produced a statistically significant decrease on pain report within the first 6 h post-operatively in the sevoflurane-based anaesthesia group (3 [2, 4] vs. 5 [4, 5], p < 0.001 in 0.5 h; 2 [0, 4] vs. 3 [3, 5], p < 0.001 in 2 h; 2 [0, 3] vs. 3 [1, 4], p = 0.002 in 4 h; 1 [0, 3] vs. 2 [1, 4], p = 0.016 in 6 h), but not in the propofol-based group. A single-dose intravenous administration of tropisetron after anaesthesia induction is associated with statistically significant decreased early post-operative pain in patients undergoing gynaecological laparoscopies under sevoflurane based general anaesthesia.
    European journal of pain (London, England) 02/2014; 18(2). DOI:10.1002/j.1532-2149.2013.00365.x · 2.93 Impact Factor
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    • "Direct support for the contribution of supraspinal sites and descending serotonergic pathways to the analgesic action of cannabinoids was derived from studies in which plant-derived tetrahydrocannabinol (THC) and synthetic cannabinoids are injected intracerebroventricularly or by microinjection into various local brain regions (Dogrul et al. 2012; Guindon and Hohmann 2009; Litchman et al. 1996). Intracerebroventricular administration of mixed CB1 and CB2 agonists, such as THC, WIN 55,212-2, and CP 55,940, and CB1 agonists, such as ACEA and methanandamide, generated dose-dependent analgesic effects in acute, inflammatory, and nerve injury models via CB1 receptors (Dogrul et al. 2012; Garzon et al. 2009; Litchman et al. 1996; Martin et al. 1993; Raffa et al. 1999; Wakley and Craft 2011; Walker and Hohmann 2005). Microinjection of cannabinoids into amygdala, PAG, RVM, nucleus reticularis gigantocellularis pars alpha, DRN, and locus coeruleus also produces antinociceptive effects in a wide array of nociceptive animal models (Litchman et al. 1996; Maione et al. 2011; Manning et al. 2003; Martin et al. 1993, 1998, 1999; Meng and Johansen 2004; Monhemius et al. 2001; Wilson-Poe et al. 2012). "
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    ABSTRACT: Plant cannabinoids have been used historically as a therapeutic agent in some folk medicine for the treatment of headache, fibromyalgia, and irritable bowel and related conditions in which serotonergic pathways are considered to play a crucial role in pathogenesis and treatment modalities. Serotonergic system has important modulatory role in acute and chronic pain conditions. The analgesic efficacy of cannabinoids in acute and chronic pain appear to be mediated, at least in part, through the regulation of the serotonergic system. In this chapter, we review the interaction between cannabinoids and serotonergic system in the peripheral, spinal and supraspinal sites with special emphasis on serotonin in central sites by which cannabinoid CB1 receptor activation reinforce descending serotonergic pathways to produce antinociceptive effects.
    Endocannabinoid Regulation of Monoamines in Psychiatric and Neurological Disorders, Edited by E. J. Van Bockstaele, 11/2013: chapter 13: pages 277-295; Springer., ISBN: 978-1-4614-7939-0
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