Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Exercise is a naturally rewarding behaviour in human beings and can be associated with feelings of euphoria and analgesia. The endocannabinoid system may play a role in the perception of neurobiological rewards during and after prolonged exercise. Mice from lines that have been selectively bred for high voluntary wheel running (high runner or HR lines) may have evolved neurobiological mechanisms that increase the incentive salience of endurance-type exercise. Here, we test the hypothesis that endocannabinoid signalling has been altered in the four replicate HR lines as compared with four nonselected control lines. After 18 days of acclimation to cages with attached wheels, we injected mice with rimonabant (SR141716), a selective cannabinoid CB1 receptor antagonist. During the time of normal peak running, each mouse received, in a randomized order, intraperitoneal injection of rimonabant (0.1 or 3.0 mg/kg) or vehicle, over 9 days. Drug response was quantified as wheel revolutions, time and speed 10-70 min postinjection. Rimonabant decreased running in all mice; however, female HR mice differentially decreased running speed and distance (but not time) as compared with control females. We conclude that altered endocannabinoid signalling plays a role in the high wheel running of female HR mice.
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PMID:Differential response to a selective cannabinoid receptor antagonist (SR141716: rimonabant) in female mice from lines selectively bred for high voluntary wheel-running behaviour. 1902 Apr 16

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

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

Substance P is thought to play an essential role in several forms of supraspinally mediated analgesia. The actions of substance P on synaptic transmission within descending analgesic pathways, however, are largely unknown. Here, we used whole-cell recordings from rat midbrain slices to examine the effects of substance P on GABAergic and glutamatergic transmission within the periaqueductal gray (PAG), a key component of a descending analgesic pathway that projects via the rostral ventromedial medulla (RVM) to the spinal cord dorsal horn. We found that substance P reversibly decreased the amplitude and increased the paired-pulse ratio of evoked IPSCs recorded from identified PAG-RVM projection neurons and from unidentified PAG neurons. Substance P had no effect on miniature IPSCs, implying an indirect mode of action. The effects of substance P were abolished by metabotropic glutamate type 5 and cannabinoid CB1 receptor antagonists, but unaltered by NMDA, GABA(B), mu,delta-opioid, adenosine A(1), and 5HT(1A) receptor antagonists. Consistent with a role for endogenous glutamate in this process, substance P increased the frequency of action potential-dependent spontaneous EPSCs. Moreover, the effect of substance P on evoked IPSCs was mimicked and occluded by a glutamate transport inhibitor. Finally, these effects were dependent on postsynaptic G-protein activation and diacylglycerol lipase activity, suggesting the requirement for retrograde signaling by the endocannabinoid 2-arachidonoylglycerol. Thus, substance P may facilitate descending analgesia in part by enhancing glutamate-mediated excitation and endocannabinoid-mediated disinhibition of PAG-RVM projection neurons.
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PMID:Substance P drives endocannabinoid-mediated disinhibition in a midbrain descending analgesic pathway. 1949 44

Cannabis contains over 70 unique compounds and its abuse is linked to an increased risk of developing schizophrenia. The behavioural profiles of the psychotropic cannabis constituent Delta9-tetrahydrocannabinol (Delta9-THC) and the non-psychotomimetic constituent cannabidiol (CBD) were investigated with a battery of behavioural tests relevant to anxiety and positive, negative and cognitive symptoms of schizophrenia. Male adult C57BL/6JArc mice were given 21 daily intraperitoneal injections of vehicle, Delta9-THC (0.3, 1, 3 or 10 mg/kg) or CBD (1, 5, 10 or 50 mg/kg). Delta9-THC produced the classic cannabinoid CB1 receptor-mediated tetrad of hypolocomotion, analgesia, catalepsy and hypothermia while CBD had modest hyperthermic effects. While sedative at this dose, Delta9-THC (10 mg/kg) produced locomotor-independent anxiogenic effects in the open-field and light-dark tests. Chronic CBD produced moderate anxiolytic-like effects in the open-field test at 50 mg/kg and in the light-dark test at a low dose (1 mg/kg). Acute and chronic Delta9-THC (10 mg/kg) decreased the startle response while CBD had no effect. Prepulse inhibition was increased by acute treatment with Delta9-THC (0.3, 3 and 10 mg/kg) or CBD (1, 5 and 50 mg/kg) and by chronic CBD (1 mg/kg). Chronic CBD (50 mg/kg) attenuated dexamphetamine (5 mg/kg)-induced hyperlocomotion, suggesting an antipsychotic-like action for this cannabinoid. Chronic Delta9-THC decreased locomotor activity before and after dexamphetamine administration suggesting functional antagonism of the locomotor stimulant effect. These data provide the first evidence of anxiolytic- and antipsychotic-like effects of chronic but not acute CBD in C57BL/6JArc mice, extending findings from acute studies in other inbred mouse strains and rats.
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PMID:A behavioural comparison of acute and chronic Delta9-tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice. 1978 14

The basolateral amygdala (BLA) contains a high density of cannabinoid CB1 receptors and is critically involved in pain and fear-related behaviour. We investigated the effects of bilateral intra-BLA administration of the CB1 receptor antagonist/inverse agonist, rimonabant, on formalin-evoked nociceptive behaviour, fear-conditioned behaviour including analgesia, and associated brain regional alterations in Fos expression in rats. Intra-BLA administration of rimonabant significantly reduced formalin-evoked nociceptive behaviour in the absence, but not presence, of conditioned fear. Rimonabant attenuated a formalin-evoked reduction in freezing while emitting 22 kHz ultrasonic vocalisation in the early part of the fear expression trial. Formalin-evoked nociceptive behaviour was associated with increased Fos immunoreactivity (FI) in the CA2/3 region of the hippocampus and rostral ventromedial medulla, effects attenuated by intra-BLA rimonabant. Formalin also decreased FI in the cingulate cortex, an effect which was not observed in fear-conditioned rats. Contextually-induced fear was associated with increased FI in the dorsal caudal periaqueductal grey in the absence, but not presence, of formalin-evoked nociceptive tone. In conclusion, bilateral intra-BLA administration of rimonabant reduces nociceptive behaviour in a model of tonic, persistent inflammatory pain, an effect associated with reduced activation of neurons in the CA2/3 hippocampus and rostral ventromedial medulla. The data also provide evidence for differential pain- and fear-related brain regional activity in the presence or absence of contextually-induced aversion and nociceptive tone.
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PMID:Effects of intra-basolateral amygdala administration of rimonabant on nociceptive behaviour and neuronal activity in the presence or absence of contextual fear. 1978 58

Delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana, and other direct cannabinoid receptor (CB1) agonists produce a number of neurobehavioral effects in mammals that range from the beneficial (analgesia) to the untoward (abuse potential). Why, however, this full spectrum of activities is not observed upon pharmacological inhibition or genetic deletion of either fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), enzymes that regulate the two major endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively, has remained unclear. Here, we describe a selective and efficacious dual FAAH/MAGL inhibitor, JZL195, and show that this agent exhibits broad activity in the tetrad test for CB1 agonism, causing analgesia, hypomotilty, and catalepsy. Comparison of JZL195 to specific FAAH and MAGL inhibitors identified behavioral processes that were regulated by a single endocannabinoid pathway (e.g., hypomotility by the 2-AG/MAGL pathway) and, interestingly, those where disruption of both FAAH and MAGL produced additive effects that were reversed by a CB1 antagonist. Falling into this latter category was drug discrimination behavior, where dual FAAH/MAGL blockade, but not disruption of either FAAH or MAGL alone, produced THC-like responses that were reversed by a CB1 antagonist. These data indicate that AEA and 2-AG signaling pathways interact to regulate specific behavioral processes in vivo, including those relevant to drug abuse, thus providing a potential mechanistic basis for the distinct pharmacological profiles of direct CB1 agonists and inhibitors of individual endocannabinoid degradative enzymes.
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PMID:Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo. 1991 51

Cannabinoid (CB) agonists exhibit numerous potentially useful pharmacological properties, but unwanted side effects limit their use in clinical practice. Thus, novel strategies are needed to identify potential CB pharmaceuticals with fewer side effects. Activated CB receptors initiate multiple parallel intracellular signal transduction cascades. In the present paper we will review experimental data indicating that structurally different classes of CB agonists may exhibit selectivity toward individual subsets of intracellular signaling pathways. In support of this, recent findings indicate that chemically distinct classes of CB agonists frequently differ in their rank order of potency to produce analgesia versus other central nervous system effects in vivo. Structurally different agonists were also found to differ in their abilities to activate individual G protein types in vitro. Since it was suggested earlier that structurally distinct CB agonists may interact differently with the CB receptors, it has been hypothesized that different classes of cannabinoid agonists may stabilize unique active CB receptor conformations, leading to functional selectivity in CB receptor signaling. In order to obtain a direct proof for this hypothesis, we recently employed a highly sensitive biophysical method, plasmon-waveguide resonance (PWR) spectroscopy. PWR experiments have provided a direct proof that structurally different CB agonists produce qualitatively distinct changes in the shape and/or membrane orientation of the CB1 receptors, leading to functional selectivity in G protein activation. We expect that by identification of CB agonists that selectively activate preferred intracellular signaling pathways novel pharmacological lead structures can be identified for the design of improved CB analgesics with fewer side effects.
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PMID:Functional selectivity in cannabinoid signaling. 2002 40

The contribution of CB1 receptors in the spinal cord to cannabinoid analgesia is still unclear. The objective of this study was to investigate the effect of CB1 receptors on substance P release from primary afferent terminals in the spinal cord. Substance P release was measured as neurokinin 1 (NK1) receptor internalization in lamina I neurons. It was induced in spinal cord slices by dorsal root stimulation and in live rats by a noxious stimulus. In spinal cord slices, the CB1 receptor antagonists AM251, AM281 and rimonabant partially but potently inhibited NK1 receptor internalization induced by electrical stimulation of the dorsal root. This was due to an inhibition of substance P release and not of NK1 receptor internalization itself, because AM251 and AM281 did not inhibit NK1 receptor internalization induced by exogenous substance P. The CB1 receptor agonist ACEA increased NK1 receptor internalization evoked by dorsal root stimulation. The effects of AM251 and ACEA cancelled each other. In vivo, AM251 injected intrathecally decreased NK1 receptor internalization in spinal segments L5 and L6 induced by noxious hind paw clamp. Intrathecal AM251 also produced analgesia to radiant heat stimulation of the paw. The inhibition by AM251 of NK1 receptor internalization was reversed by antagonists of mu-opioid and GABA(B) receptors. This indicates that CB1 receptors facilitate substance P release by inhibiting the release of GABA and opioids next to primary afferent terminals, producing disinhibition. This results in a pronociceptive effect of CB1 receptors in the spinal cord.
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PMID:Cannabinoid CB1 receptor facilitation of substance P release in the rat spinal cord, measured as neurokinin 1 receptor internalization. 2007 11


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