Pharmacological Aspects of the Effects of Tramadol on G-Protein Coupled Receptors

Minami, Kouichiro; Uezono, Yasuhito; Ueta, Yoichi

doi:10.1254/jphs.cr0060032

Cited by 56 publications

(34 citation statements)

References 55 publications

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“…Although much attention has been paid to the μ-opioid receptor and monoamine uptake in the central nervous system as targets for tramadol and ODT, several studies have shown that some GPCRs and ligand-gated ion channels are also targets for tramadol (15). In our present results, the inhibitory effects of ODT seem to be weaker than that on μ-opioid receptors and transporters.…”

Section: +contrasting

confidence: 67%

The Tramadol Metabolite O-Desmethyl Tramadol Inhibits Substance P–Receptor Functions Expressed in Xenopus Oocytes

et al. 2011

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Substance P (SP) acts as a neurotransmitter released from C fibers located within nociceptive primary afferent neurons into the spinal cord and mediates a part of the excitatory synaptic input to nociceptive neurons at this level (1). SP and its receptors (SPR) are widely distributed in the central and peripheral nervous systems (2). Several studies showed that pain sensitivity is altered in mice lacking the gene encoding SPR; a reduction in nociceptive responses to certain somatic and visceral noxious stimuli occurs in SPR knockout mice (3).SPR belongs to the family of Gq protein-coupled receptors that activate the protein kinase C (PKC) and Ca 2+-mobilization by stimulation of phospholipase C. Our recent reports have shown that the function of SPR is inhibited by volatile anesthetics and intravenous anesthetics. Halothane, isoflurane, enflurane, diethyl ether, and ethanol inhibit the function of SPR (4). Moreover, ketamine and pentobarbital inhibited the SPR-induced currents at pharmacologically relevant concentrations, whereas propofol had little effect on the currents in Xenopus oocytes expressing SPR (5). These results suggest that SPR is one of the targets of some anesthetics.O-Desmethyl tramadol (ODT) is one of the metabolites of analgesic, tramadol. Only ODT among these metabolites has been shown to have analgesic activity in mice and rats, as assessed by the tail-flick responses. Analgesic potency of ODT is 2 -4-times higher than that of tramadol (1, 3). In addition, ODT has more affinity for the μ-opioid receptor than does tramadol in biochemical receptor binding studies, although its chemical structure is quite similar to tramadol (1). There have been several reports suggesting that ODT, at pharmacologically relevant concentrations, inhibited 5-HT-evoked Ca 2+-activated Cl − currents in oocytes expressing 5-HT 2C R, and inhibited the functions of NMDA receptors, but not those of glycine and GABA A receptors (6). We have previously reported in Xenopus oocytes expressing SPR that tramadol had little effect on the SP-induced Ca 2+ -actvivated Cl − currents (5). However, a recent report has shown that tramadol, given intraperitoneally or intravenously, produced significant inhibition of the biting behavior induced by intrathecal injection of SP (7). We have previously reported the different effects on the Gq-coupled muscarinic M 3 receptors (M 3 R) between ODT and tramadol: tramadol inhibited acetylcholine (ACh)-induced currents in oocytes expressing M 3 R, whereas ODT did not. In the report we suggest that ODT does not affect the M 3 Rmediated signaling in spite of having only a small difference in its structure compared with that of tramadol (8) National Cancer Center Research Institute, Tokyo 104-0045, Japan Received December 6, 2010; Accepted January 25, 2011 Abstract. Tramadol has been widely used as analgesic. O-Desmethyl tramadol (ODT) is one of the main metabolites of tramadol, having much greater analgesic potency than tramadol itself. Substance P receptors (SPR) are well known to modulate ...

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Section: +contrasting

confidence: 67%

The Tramadol Metabolite O-Desmethyl Tramadol Inhibits Substance P–Receptor Functions Expressed in Xenopus Oocytes

et al. 2011

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“…Mechanistic aspects: Besides effects on the opioid system tramadol exerts analgesia through actions on the noradrenergic and serotonergic systems [119]. Tramadol exerts its opioid action through a metabolite (O-desmethyl-tramadol), which has an affinity for the m opioid receptor approximately 10 times lower than that of morphine [120].…”

Section: Dosementioning

confidence: 99%

Assessing analgesic actions of opioids by experimental pain models in healthy volunteers – an updated review

Staahl

Olesen

Andresen

et al. 2009

Brit J Clinical Pharma

112

131

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AIMExperimental pain models may help to evaluate the mechanisms of action of analgesics and target the clinical indications for their use. This review addresses how the efficacy of opioids can be assessed in human volunteers using experimental pain models. The drawback with the different study designs is also discussed. METHODA literature search was completed for randomized controlled studies which included human experimental pain models, healthy volunteers and opioids. RESULTSOpioids with a strong affinity for the m-opioid receptor decreased the sensation in a variety of experimental pain modalities, but strong tonic pain was attenuated more than short lasting pain and non-painful sensations. The effects of opioids with weaker affinity for the m-opioid receptor were detected by a more narrow range of pain models, and the assessment methods needed to be more sensitive. CONCLUSIONThe way the pain is induced, assessed and summarized is very important for the sensitivity of the pain models. This review gives an overview of how different opioids perform in experimental pain models. Generally experimental pain models need to be designed with careful consideration of pharmacological mechanisms and pharmacokinetics of analgesics. This knowledge can aid the decisions needed to be taken when designing experimental pain studies for compounds entering phase 1 clinical trials.

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“…Repeat dosing of a combination might lead to a build-up of an agent beyond the beneficial dose ratio or even into toxic ranges. [54] Numerous clinical studies of oral analgesics have documented the benefits of combining analgesics, however, the adverse effect profile of high-dose aspirin reduces its usefulness in combination therapy and so increasing emphasis has been placed on acetaminophen [55] Adding a NSAID to acetaminophen has been shown to improve efficacy in acute pain states; however, the additional benefit of this combination must be weighed against the increased toxicities possible with long-term NSAID use. [56] A recent trial in pediatric patients reported that there is no evidence to support combining these two drugs.…”

Section: Combination Analgesicsmentioning

confidence: 99%

Molecular Aspects of Toxicity of Centrally Acting Analgesics: A Mini Review

Samie¹

2017

WJPR

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Pain of multiple etiologies remains a significant problem for many patients presenting in the clinical setting. Improved pain relief can be maximized and adverse effects minimized, by multimodal analgesic combinations as the method to improve pain treatment. Significant suggestion supports the use of combination analgesics for the management of pain and in some cases, they have a heterogeneous pharmacologic sparing effect. Fixed-dose combination analgesics having significant efficacy and safety are extensively suitable for pain management and are usually recommended. However, further exploration is required for the best combination that which analgesics at which doses can be pooled with a co-analgesic in a patient-specific manner to attain additive, if not synergistic, multimodal pain relief with the least possible adverse values.Unsupervised intake of over-the-counter drugs offers clinical challenges to both the patient and health care providers. Couple this often unrevealed over-the-counter medication consumption event with prescription medications, which many have similar combination constituents and the potential for a therapeutic misadventure may precipitate. Patient-specific cautions are presented for opiate/opioid combinations, codeine, hydrocodone, oxycodone and propoxyphene and there is a discussion of COX I/COX II agents. This review article address the safety and efficacy of different analgesics individually and in combination with currently available prescription dosage forms with a focus on pharmacology, pharmacotherapeutics, pharmacodynamics, and pharmacokinetics, including drug interactions and toxicity profile.

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Pharmacological Aspects of the Effects of Tramadol on G-Protein Coupled Receptors

Cited by 56 publications

References 55 publications

The Tramadol Metabolite O-Desmethyl Tramadol Inhibits Substance P–Receptor Functions Expressed in Xenopus Oocytes

The Tramadol Metabolite O-Desmethyl Tramadol Inhibits Substance P–Receptor Functions Expressed in Xenopus Oocytes

Assessing analgesic actions of opioids by experimental pain models in healthy volunteers – an updated review

Molecular Aspects of Toxicity of Centrally Acting Analgesics: A Mini Review

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