Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phytocannabinoids, such as the principal bioactive component of marijuana, delta9-tetrahydrocannabinol, have been used for thousands of years for medical and recreational purposes. delta9-Tetrahydrocannabinol and endogenous cannabinoids (e.g., anandamide) initiate their agonist properties by stimulating the cannabinoid family of G protein-coupled receptors (CB1 and CB2). The biosynthesis and physiology of anandamide is well understood, but its mechanism of uptake (resulting in signal termination by fatty acid amide hydrolase) has been elusive. Mounting evidence points to the existence of a specific anandamide transport protein; however, no direct evidence for this protein has been provided. Here, we use a potent, competitive small molecule inhibitor of anandamide uptake (LY2318912, IC50 7.27 +/- 0.510 nM) to identify a high-affinity, saturable anandamide transporter binding site (LY2318912; K(d) = 7.62 +/- 1.18 nM, B(max) = 31.6 +/- 1.80 fmol/mg protein) that is distinct from fatty acid amide hydrolase. Systemic administration of the inhibitor into rodents elevates anandamide levels 5-fold in the brain and demonstrates efficacy in the formalin paw-licking model of persistent pain with no obvious adverse effects on motor function. Identification of the anandamide transporter binding site resolves a missing mechanistic link in endocannabinoid signaling, and in vivo results suggest that endocannabinoid transporter antagonists may provide a strategy for positive modulation of cannabinoid receptors.
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PMID:Identification of a high-affinity binding site involved in the transport of endocannabinoids. 1631 67

Several recent reports have demonstrated a role for selective cannabinoid CB2 receptor agonists in pain modulation, showing both analgesic and antihyperalgesic activities. While the mechanism of action is poorly understood, it has been postulated that these effects may be indirect, involving release of endogenous opioids. We have previously reported that administration of the selective cannabinoid CB2 receptor agonist GW405833 (2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]-methanone) to rats elicits potent and efficacious antihyperalgesic effects against neuropathic and inflammatory pain and, at high dose (100 mg/kg), is analgesic and ataxic [Valenzano, K.J., Tafesse, L., Lee, G., Harrison, J.E., Boulet, J., Gottshall, S.L., Mark, L., Pearson, M.S., Miller, W., Shan, S., Rabadi, L., Rotstheyn, Y., Chaffer, S.M., Turchin, P.I., Elsemore, D.A., Toth, M., Koetzner, L., Whiteside, G.T., 2005. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48, 658-672]. In the current study, we confirm these properties using mouse models and investigate the role of cannabinoid CB2 receptors using knockout animals. Furthermore, we provide evidence that the antinociceptive properties of GW405833 are opioid independent. GW405833 elicited robust antihyperalgesic effects in mouse models of inflammatory (Freund's complete adjuvant) and neuropathic (Seltzer) pain. In contrast, GW405833 showed no antihyperalgesic activity against Freund's complete adjuvant-mediated inflammatory pain in cannabinoid CB2 receptor knockout mice. As in rats, high-dose GW405833 (100 mg/kg) showed both analgesic and sedative activities in wild-type mice, activities that were also apparent in cannabinoid CB2 receptor knockout mice. In rats, neither the antihyperalgesic effect in the Freund's complete adjuvant model nor the analgesic effects in tail flick and hot plate assays were inhibited by pre-treatment with the non-selective opioid receptor antagonist, naltrexone. These data demonstrate that the antihyperalgesic effects of GW405833 are mediated via the cannabinoid CB2 receptor, whereas the analgesic and sedative effects are not. Furthermore, these data suggest that the mechanism of action for GW405833 does not depend on the release of endogenous opioids.
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PMID:A role for cannabinoid receptors, but not endogenous opioids, in the antinociceptive activity of the CB2-selective agonist, GW405833. 1631 50

The identification of peripherally expressed CB2 receptors and reports that the selective activation of cannabinoid CB2 receptors produces antinociception without traditional cannabinergic side effects suggests that selective cannabinoid CB2 receptor agonists might be useful in the management of pain. In a rat hindpaw incision model, we examined the antiallodynic activity of the selective cannabinoid CB2 receptor agonists AM1241 (3-30 mg/kg i.p.), GW405833 (3-30 mg/kg i.p.), and HU-308 (0.3-30 mg/kg i.p.). The rank order for efficacy in the hindpaw incision model following a dose of 10 mg/kg, i.p. was AM1241 > GW405833 = HU-308, and the selective cannabinoid CB2 receptor antagonist, SR144528, reversed the antiallodynic effect of HU-308. Together, these data suggest that selective cannabinoid CB2 receptor agonists might represent a new class of postoperative analgesics.
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PMID:Cannabinoid CB2 receptor agonist activity in the hindpaw incision model of postoperative pain. 1631 53

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

Clinical trial data are beginning to emerge with respect to the therapeutic efficacy of cannabis extracts for the treatment of chronic pain. Although there is some evidence of efficacy, a major issue concerns the narrow margin between doses producing therapeutic effects and those producing the "highs" associated with cannabis misuse. In addition, long-term use is associated with an increased risk of psychiatric illness. These negative aspects constrain the doses of cannabis extracts and psychoactive cannabinoids that can be given to patients, and raise the risk that properly conducted clinical trials with too low dosages will impact negatively on subsequent drug development in this field. However, recent research has opened up a number of avenues whereby compounds acting directly upon cannabinoid (CB) receptors may have therapeutic potential. In this review, two such areas are discussed, namely a) the possible use of peripherally acting CB agonists and CB2 receptor-selective agonists for the treatment of pain, and b) the possible utility of CB2 receptor agonists for the prevention of stress-induced exacerbations of skin disorders such as psoriasis. A second area of drug development at present is that of CB1 receptor antagonists/inverse agonists, spearheaded by rimonabant, for the treatment of obesity and as an aid for smoking cessation. An important aspect of these compounds is their efficacy and selectivity, and this is discussed in detail in the present review.
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PMID:Pharmacological properties and therapeutic possibilities for drugs acting upon endocannabinoid receptors. 1637 86

CB1 and CB2 cannabinoid receptors are the primary targets of endogenous cannabinoids (endocannabinoids). These G protein-coupled receptors play an important role in many processes, including metabolic regulation, craving, pain, anxiety, bone growth, and immune function. Cannabinoid receptors can be engaged directly by agonists or antagonists, or indirectly by manipulating endocannabinoid metabolism. In the past several years, it has become apparent from preclinical studies that therapies either directly or indirectly influencing cannabinoid receptors might be clinically useful. This review considers the components of the endocannabinoid system and discusses some of the most promising endocannabinoid-based therapies.
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PMID:Cannabinoid receptors as therapeutic targets. 1640

Anandamide, an endocannabinoid, is degraded by the enzyme fatty acid amide hydrolase which can be inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). The present work was designed to study the peripheral interactions between anandamide and ibuprofen (a non-specific cyclooxygenase inhibitor) in the rat formalin test. We first determined the ED50 for anandamide (0.018 microg +/- 0.009), ibuprofen (0.18 microg +/- 0.09), and their combination (0.006 microg +/- 0.002). Drugs were given 15 min before a 2.5% formalin injection into the dorsal surface of the right hind paw. Results were analyzed using isobolographic analysis. The antinociceptive interaction between anandamide and ibuprofen was synergistic. To further investigate the mechanisms by which the combination of anandamide with ibuprofen produced their antinociceptive effects, we used specific antagonists for the cannabinoid CB1 (AM251; 80 microg) and CB2 (AM630; 25 microg) receptors. We demonstrated that the antinociceptive effects of ibuprofen were not antagonized by either AM251 or AM630 and that those of anandamide were antagonized by AM251 but not by AM630. The synergistic antinociceptive effects of the combination of anandamide with ibuprofen were completely antagonized by AM251 but only partially inhibited by AM630. In conclusion, locally (hind paw) injected anandamide, ibuprofen or combination thereof decreased pain behavior in the formalin test. The combination of anandamide with ibuprofen produced synergistic antinociceptive effects involving both cannabinoid CB1 and CB2 receptors. Comprehension of the mechanisms involved needs further investigation.
Pain 2006 Mar
PMID:Local interactions between anandamide, an endocannabinoid, and ibuprofen, a nonsteroidal anti-inflammatory drug, in acute and inflammatory pain. 1648 Aug 22

The endocannabinoid system may serve important functions in the central and peripheral regulation of pain. In the present study, we investigated the effects of the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide] on rodent models of acute and persistent nociception (intraplantar formalin injection in the mouse), neuropathic pain (sciatic nerve ligation in the rat), and inflammatory pain (complete Freund's adjuvant injection in the rat). In the formalin model, administration of AM404 (1-10 mg/kg i.p.) elicited dose-dependent antinociceptive effects, which were prevented by the CB(1) cannabinoid receptor antagonist rimonabant (SR141716A; 1 mg/kg i.p.) but not by the CB2 antagonist SR144528 (1 mg/kg i.p.) or the vanilloid antagonist capsazepine (30 mg/kg i.p.). Comparable effects were observed with UCM707 [N-(3-furylmethyl)-eicosa-5,8,11,14-tetraenamide], another anandamide transport inhibitor. In both the chronic constriction injury and complete Freund's adjuvant model, daily treatment with AM404 (1-10 mg/kg s.c.) for 14 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single administration of rimonabant (1 mg/kg i.p.) and was accompanied by decreased expression of cyclooxygenase-2 and inducible nitric-oxide synthase in the sciatic nerve. The results provide new evidence for a role of the endocannabinoid system in pain modulation and point to anandamide transport as a potential target for analgesic drug development.
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PMID:Modulation of neuropathic and inflammatory pain by the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide]. 1651 Jun 98

Neuropathic pain is one of the most inextricable problems encountered in clinics, because few facts are known about its etiology. Nerve injury often leads to allodynia and hyperalgesia, which are symptoms of neuropathic pain. The aim of this study was to understand some molecular and electrophysiological mechanisms of neuropathic pain after chronic constriction of the saphenous nerve (CCS) in mice. After surgery, CCS mice displayed significant allodynia and hyperalgesia, which were sensitive to acute systemic injection of morphine (4 mg/kg), gabapentin (50 mg/kg), amitriptyline (10 mg/kg), and the cannabinoid agonist WIN 55,212-2 (5 mg/kg). These behavioral changes were accompanied after surgery by an increase of c-Fos expression and by an overexpression of mu-opioid and cannabinoid CB1 and CB2 receptors in the spinal cord and the dorsal hind paw skin. In combination with the skin-nerve preparation, this model showed a decrease in functional receptive fields downstream to the injury and the apparition of A-fiber ectopic discharges. In conclusion, CCS injury induced behavioral, molecular, and electrophysiological rearrangements that might help us in better understanding the peripheral mechanisms of neuropathic pain. This model takes advantage of the possible use in the future of genetically modified mice and of an exclusively sensory nerve for a comprehensive study of peripheral mechanisms of neuropathic pain.
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PMID:Characterization of chronic constriction of the saphenous nerve, a model of neuropathic pain in mice showing rapid molecular and electrophysiological changes. 1651 71


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