Differential mediation of descending pain facilitation and inhibition by spinal 5HT-3 and 5HT-7 receptors.
ABSTRACT 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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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 · 3.22 Impact Factor
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ABSTRACT: Tapentadol is a dual action molecule with mu opioid agonist and norepinephrine (NE) reuptake blocking activity that has recently been introduced for the treatment of moderate to severe pain. The effects of intraperitoneal (i.p.) morphine (10mg/kg), tapentadol (10 or 30mg/kg) or duloxetine (30mg/kg), a norepinephrine/serotonin (NE/5HT) reuptake inhibitor, were evaluated in male, Sprague-Dawley rats with spinal nerve ligation (SNL) or sham surgery. Additionally, the effects of these drugs on spinal cerebrospinal fluid (CSF) NE levels were quantified. Response thresholds to von Frey filament stimulation decreased significantly from baseline in SNL, but not sham, operated rats. Duloxetine, tapentadol and morphine produced significant and time-related reversal of tactile hypersensitivity. Duloxetine significantly increased spinal CSF NE levels in both sham and SNL rats and no significant differences were observed in these groups. Tapentadol (10mg/kg) produced a significant increase in spinal NE levels in SNL, but not in sham, rats. At the higher dose (30mg/kg), tapentadol produced a significant increase in spinal CSF NE levels in both SNL and sham groups; however, spinal NE levels were elevated for an extended period in the SNL rats. This could be detected 30min following tapentadol (30mg/kg) in both sham and SNL groups. Surprisingly, while the dose of morphine studied reversed tactile hypersensitivity in nerve-injured rats, CSF NE levels were significantly reduced in both sham- and SNL rats. The data suggest that tapentadol elicits enhanced elevation in spinal NE levels in a model of experimental neuropathic pain offering a mechanistic correlate to observed clinical efficacy in this pain state.Neuroscience Letters 08/2013; 562. DOI:10.1016/j.neulet.2013.08.017 · 2.06 Impact Factor
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ABSTRACT: The present study explored a link between spinal 5-HT7 and adenosine A1 receptors in antinociception by systemic amitriptyline in normal and adenosine A1 receptor knock-out mice using the 2% formalin test. In normal mice, antinociception by systemic amitriptyline 3 mg/kg was blocked by intrathecal administration of the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) 10 nmol. Blockade was also seen in adenosine A1 receptor +/+ mice, but not in −/− mice lacking these receptors. In both normal and adenosine A1 receptor +/+ mice, the selective 5-HT7 receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride (SB269970) 3 μg blocked antinociception by systemic amitriptyline, but it did not prevent antinociception in adenosine A1 receptor −/− mice. In normal mice, flinching was unaltered when the selective 5-HT7 receptor agonist (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin (AS-19) 20 μg was administered alone, but increased when co-administered intrathecally with DPCPX 10 nmol or SB269970 3 μg. Intrathecal AS-19 decreased flinching in adenosine A1 receptor +/+ mice compared to −/− mice. Systemic amitriptyline appears to reduce nociception by activating spinal adenosine A1 receptors secondarily to 5-HT7 receptors. Spinal actions constitute only one aspect of antinociception by amitriptyline, as intraplantar DPCPX 10 nmol blocked antinociception by systemic amitriptyline in normal and adenosine A1 receptor +/+, but not −/− mice. Adenosine A1 receptor interactions are worthy of attention, as chronic oral caffeine (0.1, 0.3 g/L, doses considered relevant to human intake levels) blocked antinociception by systemic amitriptyline in normal mice. In conclusion, adenosine A1 receptors contribute to antinociception by systemic amitriptyline in both spinal and peripheral compartments.European journal of pharmacology 01/2013; 698(s 1–3):213–219. DOI:10.1016/j.ejphar.2012.10.042 · 2.68 Impact Factor