Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuropathic pain, a persistent chronic pain resulting from damage to the central or peripheral pain signaling pathway, has become an area of intense research activity--largely because it represents a disorder with high unmet medical need. It is not a single disease entity, but rather includes a range of heterogeneous conditions that differ in etiology, location and initiating cause. Despite this diversity, the clinical presentation is frequently surprisingly similar, which suggests a common biological basis. Until recently, little was known of the mechanisms underlying the various neuropathic pain conditions, making the directed development of novel therapies almost impossible. However, the steady increase in our understanding of the anatomical, cellular and molecular basis of neuropathic pain, coupled with the advent of a number of experimental models of neuropathy, has permitted relatively rapid progress, and the prospects for the emergence of new, more effective therapies look very good. Gabapentin (Pfizer), which appears to act by blocking calcium channels, is the first drug to acquire widespread regulatory approval for the treatment of neuropathic pain. The Society for Medicines Research symposium held June 26, 2003, considered this treatment modality alongside other approaches to therapy, such as N-methyl-D-aspartate receptor antagonists and cannabinoid receptor agonists. The whole meeting provided an excellent description of the challenges facing neuropathic pain drug discovery--at both the research and the development phases of the value chain.
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PMID:Pharmacotherapy for neuropathic pain: progress and prospects. 1470 44

Cannabinoid receptor agonists produce analgesia for pains of non-cranial origin. However, their effectiveness for craniofacial pains is currently unclear. In the present study, the cannabinoid CB1/CB2 receptor agonist, WIN 55,212-2 (WIN), was bath applied to the brainstem while activity of spinal trigeminal nucleus caudalis (Vc) neurons evoked by transcutaneous electrical stimulation was recorded in isoflurane anesthetized rats. Neurons were characterized using mechanical and electrical stimulation of the face, and were classified as either low-threshold mechanoreceptive (LTM) or wide dynamic range (WDR). LTM neurons responded to light brushing of the receptive field and received only Abeta primary afferent fiber input. WDR neurons showed a graded response to mechanical stimulation, responding maximally to noxious stimuli, and demonstrated both A- and C-fiber evoked activity. In addition, WDR neurons displayed longer latency, C-fiber mediated post-discharge (PDC) activity after repetitive stimulation. Local bath application of 2.0 mg/ml WIN significantly reduced PDC activity (3+/-1% control, P<0.01), C-fiber evoked activity (58+/-9% control, P<0.01), and Abeta evoked activity (57+/-10% control, P<0.01) in WDR neurons. In contrast, LTM Abeta-fiber evoked activity increased after local administration of WIN (204+/-52% control, P<0.01). SR141716A, a CB1 receptor antagonist, prevented the effects of WIN on WDR PDC and LTM Abeta evoked activity. These results indicate that cannabinoid receptor agonists may be effective agents for craniofacial pain. Furthermore, the particular sensitivity of PDC activity, a measure of neuronal hyperexcitability, to cannabinoid receptor agonists may be relevant to the treatment of persistent craniofacial pain.
Pain 2004 Feb
PMID:Local application of the cannabinoid receptor agonist, WIN 55,212-2, to spinal trigeminal nucleus caudalis differentially affects nociceptive and non-nociceptive neurons. 1473 89

BOLD-contrast functional magnetic resonance imaging (fMRI) was used to investigate the effects of the synthetic cannabinoid agonist HU210 on the rat brain in order to determine potential CNS sites of action for the functional effects of cannabinoids. After obtaining basal data, rats (n=8) were given the cannabinoid agonist HU210 (10 microg/kg i.v.) and volume data sets collected for 85 mins. Significant increases in functional BOLD activity were observed in specific brain regions including those important in pain (PAG), reward (VTA and accumbens) and motor function (striatum). In order to confirm cannabinoid receptor involvement in the HU210 evoked functional BOLD activity, rats (n=8) were pre-treated with the CB1 cannabinoid receptor antagonist SR141716A (100 microg/kg i.v.) prior to HU210. Pretreatment with SR141716A abolished all significant evoked HU210 functional BOLD activity. To exclude the involvement of potential systemic effects induced by the cannabinoid agonist administration on the observed evoked functional BOLD activity a separate experiment investigated the effect of HU210 (10 microg/kg i.v.) on mean arterial pressure and showed that HU210 had no significant effect on pressure under chloral hydrate anaesthesia. In summary, this study demonstrates that the cannabinoid agonist HU210 evokes a significant increase in BOLD functional activity in specific regions and that this was cannabinoid receptor mediated. Furthermore the study indicates the potential value of fMRI in rodents to delineate pharmacologically induced changes in regional brain function.
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PMID:Detection of cannabinoid agonist evoked increase in BOLD contrast in rats using functional magnetic resonance imaging. 1497 93

Systemic administration of a cannabinoid agonist produces antinociception through the activation of pain modulating neurons in the rostral ventromedial medulla (RVM). The aim of the present study was to determine how a cannabinoid receptor agonist acting directly within the RVM affects neuronal activity to produce behaviorally measurable antinociception. In lightly anesthetized rats, two types of RVM neurons have been defined based on changes in tail flick-related activity. On-cells increase firing (on-cell burst), whereas off-cells cease firing (off-cell pause), just prior to a tail flick. The cannabinoid receptor agonist WIN55,212-2 was microinfused directly into the RVM while monitoring tail flick latencies and on- and off-cell activity. Microinfusion of WIN55,212-2 (2.0 microg/microl and 0.4 microg/microl) reduced the tail flick-related on-cell burst, decreased the duration of the off-cell pause, and increased off-cell ongoing activity. These changes were prevented by co-infusing the CB1 receptor antagonist, SR141716A (0.35 microg/microl), with WIN55,212-2 (0.4 microg/microl). Furthermore, 2.0 microg/microl WIN55,212-2 delayed the onset of the off-cell pause and increased tail flick latencies. Microinfusion of WIN55,212-2 to brain regions caudal or lateral to the RVM had no effect on RVM neuronal activity or tail flick latencies. These results indicate that cannabinoids act directly within the RVM to affect off-cell activity, providing one mechanism by which cannabinoids produce antinociception.
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PMID:Antinociception and modulation of rostral ventromedial medulla neuronal activity by local microinfusion of a cannabinoid receptor agonist. 1498 Jul 38

Growing basic research in recent years led to the discovery of the endocannabinoid system with a central role in neurobiology. New evidence suggests a therapeutic potential of cannabinoids in cancer chemotherapy-induced nausea and vomiting as well as in pain, spasticity and other symptoms in multiple sclerosis and movement disorders. Results of large randomized clinical trials of oral and sublingual Cannabis extracts will be known soon and there will be definitive answers to whether Cannabis has any therapeutic potential. Although the immediate future may lie in plant-based medicines, new targets for cannabinoid therapy focuses on the development of endocannabinoid degradation inhibitors which may offer site selectivity not afforded by cannabinoid receptor agonists.
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PMID:[News about therapeutic use of Cannabis and endocannabinoid system]. 1503 46

Bayer AG has recently announced that it acquired exclusive rights for the marketing of GW Pharmaceuticals' new medicine Sativex in Europe and in other regions. Sativex is a sublingual spray on Cannabis extract basis, and is equipped with an electronic tool to facilitate accurate dosing and to prevent misuses. It is standardized for the THC and CBD. The new analgesic is proposed for the treatment of muscle spasticity and pains accompanying multiple sclerosis and as an efficient analgetic for neurogenic pain not responding well to opioids and to other therapies available. The entirely new mechanism of action through the recently discovered cannabinoid receptor system may offer a real therapeutic potential to the drug. Although the Government of Netherlands has authorized the sale of pharmaceutical grade Cannabis herb by pharmacies in the Netherlands, the availability on the pharmaceutical market of the registered preparation may render requests for the authorization of the smoking of Cannabis herb (marihuana) by individuals suffering of multiple sclerosis, neurogenic pain, AIDS wasting syndrome unnecessary. Nevertheless, the "old chameleon" plant Cannabis appears to gradually regain its previous status in mainstream therapy and pharmacy. As long as the plant Cannabis and its products continue to be classified as narcotic drugs, medical use of the new preparation will need close supervision.
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PMID:[A novel analgesics made from Cannabis]. 1504 67

The roles of the two cannabinoid receptor subtypes, CB-1 and CB-2, have not been clarified in cannabinoid-mediated analgesia. We investigated the efficacy of the non-selective cannabinoid receptor agonist CP55,940 in the modulation of responses in the rat to both acute pain (tail flick) and neuropathic pain (tactile allodynia following chronic L5/6 spinal nerve ligation). Responses were also assessed in the presence of the CB-1 antagonist SR141716A (SR1) and the CB-2 antagonist SR144528 (SR2). CP55,940 attenuated tactile allodynia (ED(50) 0.04 mg/kg i.t. (95% CI 0.032-0.044 mg/kg), 0.12 mg/kg i.p. (95% CI 0.10-0.15 mg/kg)) and induced thermal antinociception (ED(50) tail flick 0.07 mg/kg i.t. (95% CI 0.05-0.10 mg/kg), 0.17 mg/kg i.p. (95% CI 0.11-0.26 mg/kg)). SR1 0.5 mg/kg i.t. attenuated the antinociceptive effect of CP55,940 in both modalities. However, SR1 1.0 mg/kg i.p. decreased tail flick latency but had no effect on tactile allodynia antinociception. In contrast, SR2 1.0 mg/kg i.p. significantly decreased the effect of i.p. CP55,940 on both tail flick antinociception and tactile allodynia (P<0.005). The combination of SR1 and SR2 (i.p.) had an additive effect in decreasing the antinociception induced by CP55,940 on tail flick responses (P<0.005). These results suggest a role for CB-2 receptor-mediated antinociception in both acute and neuropathic pain in addition to centrally located CB-1 mechanisms.
Pain 2004 May
PMID:Evidence that CB-1 and CB-2 cannabinoid receptors mediate antinociception in neuropathic pain in the rat. 1508 34

From a historical perspective to the present day, all the evidence suggests that activation of cannabinoid receptors (CBRs) is beneficial for gut discomfort and pain, which are symptoms related to dysmotility and visceral perception. CBRs comprise G-protein coupled receptors that are predominantly in enteric and central neurones (CB1R) and immune cells (CB2R). In the last decade, evidence obtained from the use of selective agonists and inverse agonists/antagonists indicates that manipulation of CB1R can alter (1) sensory processing from the gut, (2) brain integration of brain-gut axis, (3) extrinsic control of the gut and (4) intrinsic control by the enteric nervous system. The extent to which activation of CB1R is most critical at these different levels is related to the region of the GI tract. The upper GI tract is strongly influenced by CB1R activation on central vagal pathways, whereas intestinal peristalsis can be modified by CB1R activation in the absence of extrinsic input. Actions at multiple levels make the CB1R a target for the treatment of functional bowel disorders, such as IBS. Since low-grade inflammation may act as a trigger for occurrence of IBS, CB2R modulation could be beneficial, but there is little supporting evidence for this yet. The challenge is to accomplish CBR activation while minimizing adverse effects and abuse liabilities. Potential therapeutic strategies involve increasing signaling by endocannabinoids (EC). The pathways involved in the biosynthesis, uptake and degradation of EC provide opportunities for modulation of CB1R and some recent evidence with inhibitors of EC uptake and metabolism suggest that these could be exploited for therapeutic gain.
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PMID:Involvement of cannabinoid receptors in gut motility and visceral perception. 1510 Jan 66

Although the N-arachidonoyl ethanolamine (anandamide) binds to cannabinoid receptors and has been implicated in the suppression of pain, its rapid catabolism in vivo by fatty acid amide hydrolase (FAAH) has presented a challenge in investigating the physiological functions of this endogenous cannabinoid. In order to test whether anandamide and other non-cannabinoid fatty amides modulate nociception, we compared FAAH (+/+) and (-/-) mice in the tail immersion, hot plate, and formalin tests, as well as for thermal hyperalgesia in the carrageenan and the chronic constriction injury (CCI) models. FAAH (-/-) mice exhibited a CB1 receptor-mediated phenotypic hypoalgesia in thermal nociceptive tests. These mice also exhibited CB1 receptor-mediated hypoalgesia in both phases of the formalin test accompanied with a phenotypic anti-edema effect, which was not blocked by either CB1 or CB2 antagonists. Additionally, FAAH (-/-) mice displayed thermal anti-hyperalgesic and anti-inflammatory effects in the carrageenan model that were mediated, in part, by CB2, but not CB1 receptors. In contrast, no genotype differences in pain behavior were evident following CCI, which was instead found to obliterate the phenotypic hypoalgesia displayed by FAAH (-/-) mice in the tail immersion and hot plate tests, suggesting that nerve injury may promote adaptive changes in these animals. Collectively, these findings demonstrate a cannabinoid receptor-mediated analgesic phenotype in FAAH (-/-) mice. In more general terms, these findings suggest that selective inhibitors of FAAH might represent a viable pharmacological approach for the clinical treatment of pain disorders.
Pain 2004 Jun
PMID:Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia. 1515 93

Accumulating evidence suggests that cannabinoids can produce antinociception through peripheral mechanisms. In the present study, we determined whether cannabinoids attenuated existing hyperalgesia produced by a mild heat injury to the glabrous hindpaw and whether the antihyperalgesia was receptor-mediated. Anesthetized rats received a mild heat injury (55 degrees C for 30 s) to one hindpaw. Fifteen minutes after injury, animals exhibited hyperalgesia as evidenced by lowered withdrawal latency to radiant heat and increased withdrawal frequency to a von Frey monofilament (200 mN force) delivered to the injured hindpaw. Separate groups of animals were then treated with an intraplantar (i.pl.) injection of vehicle or the cannabinoid receptor agonist WIN 55,212-2 at doses of 1, 10, or 30 microg in 100 microl. WIN 55,212-2 attenuated both heat and mechanical hyperalgesia dose-dependently. The inactive enantiomer WIN 55,212-3 did not alter mechanical or heat hyperalgesia, suggesting the effects of WIN 55,212-2 were receptor-mediated. The CB1 receptor antagonist AM 251 (30 microg) co-injected with WIN 55,212-2 (30 microg) attenuated the antihyperalgesic effects of WIN 55,212-2. The CB2 receptor antagonist AM 630 (30 microg) co-injected with WIN 55,212-2 attenuated only the early antihyperalgesic effects of WIN 55,212-2. I.pl. injection of WIN 55,212-2 into the contralateral paw did not alter the heat-injury induced hyperalgesia, suggesting that the antihyperalgesia occurred through a peripheral mechanism. These data demonstrate that cannabinoids primarily activate peripheral CB1 receptors to attenuate hyperalgesia. Activation of this receptor in the periphery may attenuate pain without causing unwanted side effects mediated by central CB1 receptors.
Pain 2004 Jun
PMID:Activation of peripheral cannabinoid receptors attenuates cutaneous hyperalgesia produced by a heat injury. 1515 4


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