Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While cannabinoid receptor agonists have analgesic activity in chronic pain states, they produce a spectrum of central CB(1) receptor-mediated motor and psychotropic side effects. The actions of endocannabinoids, such as anandamide are terminated by removal from the extracellular space, then subsequent enzymatic degradation by fatty-acid amide hydrolase (FAAH). In the present study, we compared the effect of a selective FAAH inhibitor, URB597, to that of a pan-cannabinoid receptor agonist HU210 in rat models of chronic inflammatory and neuropathic pain. Systemic administration of URB597 (0.3 mg kg(-1)) and HU210 (0.03 mg kg(-1)) both reduced the mechanical allodynia and thermal hyperalgesia in the CFA model of inflammatory pain. In contrast, HU210, but not URB597, reduced mechanical allodynia in the partial sciatic nerve-ligation model of neuropathic pain. HU210, but not URB597, produced a reduction in motor performance in unoperated rats. The effects of URB597 in the CFA model were dose dependent and were reduced by coadministration with the cannabinoid CB1 antagonist AM251 (1 mg kg(-1)), or the CB2 and SR144528 (1 mg kg(-1)). Coadministration with AM251 plus SR144528 completely reversed the effects of URB597. These findings suggest that the FAAH inhibitor URB597 produces cannabinoid CB1 and CB2 receptor-mediated analgesia in inflammatory pain states, without causing the undesirable side effects associated with cannabinoid receptor activation.
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PMID:Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models. 1633 Dec 91

Endocannabinoid circuits have been shown to regulate a number of important pathways including pain, feeding, memory and motor coordination. Direct manipulation of endocannabinoid tone, therefore, may relieve disease symptoms related to analgesia, obesity, Alzheimer's and Parkinson's in humans. The endocannabinoid circuit involves two cloned receptors: CB1 in the CNS and CB2 in the periphery; endogenously produced ligands including anandamide, 2-arachidonylglycerol and palmitoylethanolamide; and enzymes that degrade endocannabinoid ligands to terminate signaling. Currently, three enzymes have been characterized with the ability to hydrolyze endocannabinoids: fatty acid amide hydrolase (FAAH), monoglyceride lipase (MGL) and N-acylethanolamine-hydrolyzing acid amidase (NAAA). The purpose of this review is to examine the molecular biology for the enzymes that hydrolyze endocannabinoids covering the protein activity and expression, mRNA characterization, genomic locus organization, promoter analysis and knockout phenotypes.
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PMID:Molecular biology of the enzymes that degrade endocannabinoids. 1637 80

Cannabinoid CB1 and CB2 receptors are located at key sites involved in the relaying and processing of noxious inputs. Both CB1 and CB2 receptor agonists have analgesic effects in a range of models of inflammatory and neuropathic pain. Importantly, clinical trials of cannabis-based medicines indicate that the pre-clinical effects of cannabinoid agonists may translate into therapeutic potential in humans. One of the areas of concern with this pharmacological approach is that CB1 receptors have a widespread distribution in the brain and that global activation of CB1 receptors is associated with adverse side effects. Studies of the endogenous cannabinoids (endocannabinoids) have demonstrated that they are present in most tissues and that in some pain states, such as neuropathic pain, levels of endocannabinoids are elevated at key sites involved in pain processing. An alternative approach that can be used to harness the potential therapeutic effects of cannabinoids is to maximise the effects of the endocannabinoids, the actions of which are terminated by re-uptake and metabolism by various enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL) and cyclooxygenase type 2 (COX2). Preventing the metabolism, or uptake, of endocannabinoids elevates levels of these lipid compounds in tissue and produces behavioural analgesia in models of acute pain. Herein we review recent studies of the effects of inhibition of metabolism of endocannabinoids versus uptake of endocannabinoids on nociceptive processing in models of inflammatory and neuropathic pain.
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PMID:Endocannabinoid metabolism and uptake: novel targets for neuropathic and inflammatory pain. 1789 Nov 56

Delta9-tetrahydrocannabinol is the active component in cannabis and has long been associated with pain relief. This effect is believed to be mediated through central and peripheral CB1 and peripheral CB2 receptors. We have explored the possible antinociceptive effect of a CB2 receptor agonist, JWH133, using the formalin test in mice. The drug was administered by the intracerebroventricular and intraperitoneal routes. Although no antinociceptive effect was observed after intracerebroventricular administration of JWH133, when the drug was administered by the intraperitoneal route, it produced an analgesic effect. The influence of nicotinic cholinergic receptor modulators, nicotine and mecamylamine, on antinociceptive effect of JWH133 was also studied. Nicotine increased and mecamylamine decreased the antinociceptive effect of JWH133. It is concluded that JWH133-induced analgesia is influenced by nicotinic cholinergic receptor activity.
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PMID:Influence of nicotinic receptor modulators on CB2 cannabinoid receptor agonist (JWH133)-induced antinociception in mice. 1791 54

2-Arachidonoylglycerol (2-AG) and anandamide are endocannabinoids that activate the cannabinoid receptors CB1 and CB2. Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that for anandamide is mediated by fatty acid amide hydrolase (FAAH), and for 2-AG is thought to involve monoacylglycerol lipase (MAGL). FAAH inhibitors produce a select subset of the behavioral effects observed with CB1 agonists, which suggests a functional segregation of endocannabinoid signaling pathways in vivo. Testing this hypothesis, however, requires specific tools to independently block anandamide and 2-AG metabolism. Here, we report a potent and selective inhibitor of MAGL called JZL184 that, upon administration to mice, raises brain 2-AG by eight-fold without altering anandamide. JZL184-treated mice exhibited a broad array of CB1-dependent behavioral effects, including analgesia, hypothermia and hypomotility. These data indicate that 2-AG endogenously modulates several behavioral processes classically associated with the pharmacology of cannabinoids and point to overlapping and unique functions for 2-AG and anandamide in vivo.
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PMID:Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. 1908 12

Availability of selective pharmacological tools enabled a great advance of our knowledge of cannabinoid receptor 2 (CB2) role in pathophysiology. In particular CB2 emerged as an interesting target for chronic pain treatment as demonstrated by several studies on inflammatory and neuropathic preclinal pain models. The mechanisms at the basis of CB2-mediated analgesia are still controversial but data are pointing out in two main directions: an effect on inflammatory cells and/or an action on nociceptors and spinal cord relay centers. In this review will be described the second messenger pathways activated by CB2 agonists, the data underpinning the analgesic profile of CB2 selective agonists and the mechanisms invoked to explain their analgesic action. Finally the ongoing clinical trials and the potential issues for the development of a CB2 agonist drug will be examined.
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PMID:Cannabinoid type 2 receptor as a target for chronic - pain. 1914 57

Our understanding of the complexity of the endocannabinoid system has evolved considerably since the cloning of the receptors in the early 1990s. Since then several endogenous ligands have been identified and their respective biosynthetic pathways unravelled. This research has revealed the involvement of the cannabinoid system in a number of important physiological processes including the regulation of neurotransmitter release, pain and analgesia, energy homeostasis, and control of immune cell function. All of these events are mediated by two similar receptors, CB1 and CB2, which were initially thought to possess mutually exclusive expression profiles. Recent advances have begun to dissolve such absolutes with the discovery of CB2 in brain tissue and identification of a range of functions for CB1 in peripheral tissues. With improved understanding of the cannabinoid system comes the illumination of various roles in disease pathologies and identification of potential therapeutic targets. This review provides an overview of the current understanding of the endocannabinoid system, and then focuses on recent discoveries that we believe are likely to shape the future directions of the field.
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PMID:Cannabinoid Receptors: A brief history and what not 1927 10

Orofacial pain disorders are frequent in the general population and their pharmacological treatment is not always adequately resolved. Cannabinoids have demonstrated their analgesic effect in several pain conditions, both in animal models and in clinical situations. The aim of the present study was to evaluate the cannabinoid-mediated antinociception in two inflammatory models of orofacial pain (orofacial and temporomandibular joint (TMJ) formalin test) and to compare it with a spinal inflammatory model (paw formalin test). WIN 55,212-2 (0.5, 1mg/kg), a synthetic cannabinoid agonist, was intraperitoneally (i.p.) administered prior to formalin and significantly reduced the nociceptive behavioural responses in these inflammatory tests. To elucidate which subtype of receptor could be involved in such effect, two selective cannabinoid antagonists were administered prior to WIN. SR141716A (1mg/kg i.p.), the CB1 receptor-selective antagonist, was able to prevent the cannabinoid-induced analgesia in all three models, whereas SR144528 (1mg/kg i.p.), the CB2 receptor-selective antagonist, only prevented it in the paw formalin test. A comparison with the antinociceptive effects of morphine (2.5, 5, 10mg/kg, i.p.), indomethacin (2.5, 5mg/kg, i.p.) and ketamine (25, 50mg/kg, i.p.) was also performed. Morphine displayed a dose-dependent reduction of acute and inflammatory pain in all three models, whereas indomethacin and ketamine only attenuated inflammatory pain at the highest tested doses. These results indicate that the cannabinoid-induced antinociception in the orofacial region is mediated by activation of CB1 cannabinoid receptor. Moreover WIN was as effective as morphine and more effective than indomethacin and ketamine, in oral inflammatory pain.
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PMID:Antinociceptive effect of the cannabinoid agonist, WIN 55,212-2, in the orofacial and temporomandibular formalin tests. 1931 83

Cholestasis is associated with increased activity of the endogenous opioid system that results in analgesia. Endocannabinoid system can reduce pain sensitivity. Considering the interaction that has been shown between the endogenous opioid and endocannabinoid systems in nociception processing, we studied the effect of AM404, an endocannabinoid transport inhibitor, on modulation of nociception in cholestasis, a model of elevated endogenous opioid tone. Cholestasis was induced by ligation of the main bile duct using two ligatures and transection of the duct at the midpoint between them. A significant increase (P<0.01) in TF was observed in cholestatic rats compared to unoperated and sham rats. AM404 (10 mg/kg, i.p.) significantly increased TFL at 5, 30 min but not 60 min after injection in cholestatic animals compared to the vehicle treated cholestatic group (P<0.05, P<0.001, respectively). AM404 injection to unoperated and sham rats did not alter baseline TFL. The effect of AM404 in cholestatic rats was blocked by co-administration of a CB(1) receptor antagonist, AM251 (1 mg/kg, i.p.) but not by the CB2 receptor antagonist, SR144528 (1 mg/kg, i.p.). Naloxone injection blocked the antinociception induced by cholestasis in bile duct ligated group. Antinociception produced by injection of AM404 in cholestatics was also attenuated by co-administration of naloxone. These data show that AM404 potentiates antinociception induced by cholestasis and indicate that there are possible interactions between opioid and cannabinoid systems in this experimental model of elevated endogenous opioid tone. The inhibitory effects of AM404 in this model are mediated by cannabinoid CB(1) and not CB(2) receptors.
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PMID:The endocannabinoid transport inhibitor AM404 modulates nociception in cholestasis. 1961 63

Cannabinoids are analgesic in man, but their use is limited by their psychoactive properties. One way to avoid cannabinoid receptor subtype 1 (CB1R)-mediated central side-effects is to develop CB1R agonists with limited CNS penetration. Activation of peripheral CB1Rs has been proposed to be analgesic, but the relative contribution of peripheral CB1Rs to the analgesic effects of systemic cannabinoids remains unclear. Here we addressed this by exploring the analgesic properties and site of action of AZ11713908, a peripherally restricted CB1R agonist, in rodent pain models. Systemic administration of AZ11713908 produced robust efficacy in rat pain models, comparable to that produced by WIN 55, 212-2, a CNS-penetrant, mixed CB1R and CB2R agonist, but AZ11713908 generated fewer CNS side-effects than WIN 55, 212-in a rat Irwin test. Since AZ11713908 is also a CB2R inverse agonist in rat and a partial CB2R agonist in mouse, we tested the specificity of the effects in CB1R and CB2R knock-out (KO) mice. Analgesic effects produced by AZ11713908 in wild-type mice with Freund's complete adjuvant-induced inflammation of the tail were completely absent in CB1R KO mice, but fully preserved in CB2R KO mice. An in vivo electrophysiological assay showed that the major site of action of AZ11713908 was peripheral. Similarly, intraplantar AZ11713908 was also sufficient to induce robust analgesia. These results demonstrate that systemic administration of AZ11713908, produced robust analgesia in rodent pain models via peripheral CB1R. Peripherally restricted CB1R agonists provide an interesting novel approach to analgesic therapy for chronic pain.
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PMID:A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain. 2069 25


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