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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cannabinoids are the constituents of the marijuana plants. The central effects of exogenous cannabinoids are implicated in enhancing mood, altering emotional states, and interfering in the formation of short-term memory. Cannabinoid receptors are G protein-coupled receptors with seven transmembrane domains that are expressed on the cell surface with their binding domain exposed to the extracellular space. To date, two cannabinoid receptors have been cloned, CB1 and CB2. Recent evidence suggests that a third CB3 receptor is out there, waiting to be cloned. The endocannabinoids may represent the first members of a new classes of neuromodulators, that are not stored in cell vesicles, but rather synthesised by the cell on demand. The endogenous cannabinoid system could play a central role in several neuropsychiatric disorders and is also involved in other conditions such as pain, spasticity and neuroprotection. Implication of cannabinoid system in the pathogenesis and development of schizophrenia is also discussed.
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PMID:Cannabinoid receptors and their relationships with neuropsychiatric disorders. 1569 7

For about 5,000 years, cannabis has been used as a therapeutic agent. There has been growing interest in the medical use of cannabinoids. This is based on the discovery that cannabinoids act with specific receptors (CB1 and CB2). CB1 receptors are located in specific brain areas (e.g. cerebellum, basal ganglia, and hippocampus) and CB2 receptors on cells of the immune system. Endogenous ligands of the cannabinoid receptors were also discovered (e.g. anandamids). Many physiologic processes are modulated by the two subtypes of cannabinoid receptor: motor functions, memory, appetite, and pain. These innovative neurobiologic/pharmacologic findings could possibly lead to the use of synthetic and natural cannabinoids as therapeutic agents in various areas. Until now, cannabinoids were used as antiemetic agents in chemotherapy-induced emesis and in patients with HIV-wasting syndrome. Evidence suggests that cannabinoids may prove useful in some other diseases, e.g. movement disorders such as Gilles de la Tourette's syndrome, multiple sclerosis, and pain. These new findings also explain the acute adverse effects following cannabis use.
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PMID:[The endogenous cannabinoid system. Therapeutic implications for neurologic and psychiatric disorders]. 1577 59

To date, two cannabinoid receptors have been identified, CB1 and CB2. Activation of these receptors with non-selective cannabinoid receptor agonists reduces pain sensitivity in animals and humans. However, activation of CB1 receptors is also associated with central side effects, including ataxia and catalepsy. More recently, a role for selective CB2 agonists in pain modification has been demonstrated. GW405833, a selective CB2 agonist, was recently reported to partially reverse the inflammation and hyperalgesia in a rat model of acute inflammation. In the current report, we extend the characterization and therapeutic potential of this compound. For the first time, we show that GW405833 selectively binds both rat and human CB2 receptors with high affinity, where it acts as a partial agonist (approximately 50% reduction of forskolin-mediated cAMP production compared to the full cannabinoid agonist, CP55,940). We also report for the first time that intraperitoneal administration of GW405833 (0.3-100 mg/kg) to rats shows linear, dose-dependent increases in plasma levels and substantial penetration into the central nervous system. In addition, GW405833 (up to 30 mg/kg) elicits potent and efficacious antihyperalgesic effects in rodent models of neuropathic, incisional and chronic inflammatory pain, the first description of this compound in these models. In contrast, analgesia, sedation and catalepsy were not observed in this dose range, but were apparent at 100 mg/kg. Additionally, GW405833 was not antihyperalgesic against chronic inflammatory pain in CB2 knockout mice. These data support the tenet that selective CB2 receptor agonists have the potential to treat pain without eliciting the centrally-mediated side effects associated with non-selective cannabinoid agonists, and highlight the utility of GW405833 for the investigation of CB2 physiology.
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PMID:Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. 1581 1

Since the discovery of anandamide in 1992, our knowledge of the endocannabinoid system and its physiological effects has increased greatly, not the least as a result of the availability of compounds affecting endocannabinoid function. In the present review, the pharmacology of the endocannabinoid system is discussed. At present, there are no compounds selectively inhibiting the synthesis of anandamide, and the mechanisms by which anandamide release and reuptake are blocked are a matter for current debate. In contrast, selective agonists and inverse agonists at the CB1 and CB2 receptors have been well characterised, as have inhibitors of the metabolism of anandamide by fatty acid amide hydrolase. Accumulating evidence has suggested that such compounds may be useful for the treatment of a number of disorders. With respect to the treatment of pain, topical CB1 agonists and CB2 agonists may prove therapeutically useful, and there is evidence that the non-steroidal inflammatory agent indomethacin produces effects secondary to activation of the endocannabinoid system. Modulation of the endocannabionid system may also produce neuroprotective effects, although present data would suggest that the observed effects are highly dependent upon the nature of the neurotoxic insult.
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PMID:The endocannabinoid signaling system: pharmacological and therapeutic aspects. 1593 56

CT-3 (ajulemic acid) is a synthetic analogue of a metabolite of Delta9-tetrahydrocannabinol that has reported analgesic efficacy in neuropathic pain states in man. Here we show that CT-3 binds to human cannabinoid receptors in vitro, with high affinity at hCB1 (Ki 6 nM) and hCB2 (Ki 56 nM) receptors. In a functional GTP-gamma-S assay CT-3 was an agonist at both hCB1 and hCB2 receptors (EC50 11 and 13.4 nM, respectively). In behavioural models of chronic neuropathic and inflammatory pain in the rat, oral administration of CT-3 (0.1-1 mg/kg) produced up to 60% reversal of mechanical hyperalgesia. In both models the antihyperalgesic activity was prevented by the CB1-antagonist SR141716A but not the CB2-antagonist SR144528. In the tetrad of tests for CNS activity, CT-3 (1-10 mg/kg, po) produced dose-related catalepsy, deficits in locomotor performance, hypothermia, and acute analgesia. Comparison of 50% maximal effects in the tetrad and chronic pain assays produced an approximate therapeutic index of 5-10. Pharmacokinetic analysis showed that CT-3 exhibits significant but limited brain penetration, with a brain/plasma ratio of 0.4 measured following oral administration, compared to ratios of 1.0-1.9 measured following subcutaneous administration of WIN55,212-2 or Delta9-THC. These data show that CT-3 is a cannabinoid receptor agonist and is efficacious in animal models of chronic pain by activation of the CB1 receptor. Whilst it shows significant cannabinoid-like CNS activity, it exhibits a superior therapeutic index compared to other cannabinoid compounds, which may reflect a relatively reduced CNS penetration.
Pain 2005 Jul
PMID:Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat. 1593 83

An increasing number of cannabinoid actions are being reported that do not appear to be mediated by either CB1 or CB2, the known cannabinoid receptors. One such example is the synthetic analog ajulemic acid (AJA), which shows potent analgesic and anti-inflammatory effects in rodents and humans. AJA binds weakly to CB1 only at concentrations many fold higher than its therapeutic range, and is, therefore, completely free of psychotropic effects in both normal subjects and pain patients suggesting the involvement of a target site other than CB1. AJA as well as several other cannabinoids appear to have profound effects on cellular lipid metabolism as evidenced by their ability to transform fibroblasts into adipocytes where the accumulation of lipid droplets can be readily observed. Such transformations can be mediated by the activation of the nuclear receptor PPAR-gamma. A variety of small molecule ligands including AJA have been shown to induce the activation of PPAR-gamma and, in some cases this has led to the introduction of clinically useful agents. It is suggested that PPAR-gamma may serve a receptor function for certain actions of some cannabinoids.
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PMID:PPAR-gamma: a nuclear receptor with affinity for cannabinoids. 1600 6

The endocannabinoids are lipid messengers that engage the same cell surface receptors targeted by delta9-tetrahydrocannabinol, the active component of marijuana. They are produced by cells in the brain and other tissues and combine with two subtypes of G protein-coupled cannabinoid receptors, CB1 and CB2. Their ability to modulate a variety of pathophysiological processes, including appetite, pain and mood, provides unique opportunities for drug discovery. Three such opportunities are discussed here: reduction of body weight through blockade of CB1 receptors, alleviation of pain through activation of extracerebral cannabinoid receptors, and modulation of pain and anxiety through inhibition of endocannabinoid degradation.
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PMID:The endocannabinoid system: a drug discovery perspective. 1604 62

Paclitaxel is an effective antineoplastic drug treatment used as an anti-tumoral therapy. Unfortunately its use is associated with unwanted side effects, which include the development of peripheral neuropathies and neuropathic pain, greatly affecting the quality of life of patients. It is well known that agonists of the cannabinoid receptor are able to reduce hyperalgesia and allodynia that develop after nerve injury. Our aim was to evaluate the efficacy of the cannabinoid agonist WIN 55,212-2 to reduce the thermal hyperalgesia and the tactile allodynia induced by administration of paclitaxel in rats. Present results demonstrate that WIN 55,212-2 (1 mg/kg i.p.) significantly reduced the heat (P<0.0001) and the mechanical (P=0.0003) withdrawal thresholds, the dose being smaller than that required to reach similar effects in the sciatic nerve constriction model (1.5 mg/kg). When the cannabinoid tetrad test was evaluated to measure behavioral modifications, it was found that WIN 55,212-2 (1mg/kg) did not induce changes either in body temperature or in immobility time, and only a reduction in spontaneous motility was recorded. This effect was antagonized by SR 141716A, suggesting the involvement of the CB1 receptor, although the participation of CB2 receptors cannot be excluded from this study. When WIN 55,212-2 was administered intraplantar, no differences were observed between the injected paw and the contralateral paw, suggesting that systemic mechanisms are needed to reach effectiveness. From these results we suggest that cannabinoids may be an interesting alternative to reduce neuropathic symptoms induced by paclitaxel, however more work is required to assess this possibility.
Pain 2005 Nov
PMID:A cannabinoid agonist, WIN 55,212-2, reduces neuropathic nociception induced by paclitaxel in rats. 1620 94

Anandamide, the ethanolamide of arachidonic acid, is an endogenous cannabinoid. It is an agonist at CB1 and CB2 cannabinoid receptors as well as the vanilloid receptor, VR1. It is analgesic in inflammatory and neuropathic pain. Both central and peripheral mechanisms are considered to participate in its analgesia. Primary sensory neurons express Na+ currents that are involved in the pathogenesis of pain. We examined the effect of anandamide on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Na+ currents in rat dorsal root ganglion neurons. Anandamide inhibited both Na+ currents in a concentration-dependent manner. At a membrane potential of -80 mV, the current inhibition was greater in TTX-S than TTX-R currents (K(d); 5.4 microM vs. 38.4 microM). The activation and inactivation became faster in TTX-R current but not in TTX-S current. Anandamide did not alter the activation voltage in either type of current. It, however, produced a hyperpolarizing shift of the steady-state inactivation voltage in both types of currents. The maximum availability at a large negative potential was not reduced by anandamide. Thus, anandamide seems to affect inactivated Na+ channels rather than resting channels. The inhibition of Na+ currents was not reversed by AM 251 (a CB1 antagonist), AM 630 (a CB2 antagonist) or capsazepine (a VR1 antagonist), suggestive of a direct action of anandamide on Na+ channels. The inhibition of Na+ currents in sensory neurons may contribute to the anandamide analgesia.
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PMID:Anandamide suppression of Na+ currents in rat dorsal root ganglion neurons. 1625 60

The aim of the present study was to investigate the effects of cannabinoid agonists on established inflammatory hyperalgesia. We have compared the effects of pre-administration versus post-administration of a potent non-selective cannabinoid agonist HU210 and a selective CB2 receptor agonist JWH-133 on hindpaw weight bearing and paw oedema in the carrageenan model of inflammatory hyperalgesia. For comparative purposes we also determined the effects of the mu-opioid receptor agonist morphine and the COX2 inhibitor rofecoxib in this model. At 3 h following intraplantar injection of carrageenan (2%, 100 microl) there was a significant (P < 0.001) reduction in weight bearing on the ipsilateral hindpaw, compared to vehicle treated rats and a concomitant increase in ipsilateral hindpaw volume (P < 0.001), compared to vehicle treated rats. Systemic administration of HU210 (10 microg/kg) and JWH-133 (10 mg/kg) at 3 h following injection of carrageenan, significantly attenuated decreases in ipsilateral hindpaw weight bearing (P < 0.05 for both) and paw volume (P < 0.001 for both). Pre-administration of HU210 and JWH-133 had similar effects on weight bearing in this model. Pre-administered HU210 also significantly decreased carrageenan-induced changes in paw volume (P < 0.001), this was not the case for JWH-133. Effects of post-administered HU210 and JWH-133 on ipsilateral hindpaw weight bearing and paw volume were comparable to the effect of systemic post-administration of morphine and rofecoxib (3 mg/kg for both). In summary, both HU210 and JWH-133 attenuated established inflammatory hypersensitivity and swelling, suggesting that cannabinoid-based drugs have clinical potential for the treatment of established inflammatory pain responses.
Pain 2005 Dec 05
PMID:Activation of CB1 and CB2 receptors attenuates the induction and maintenance of inflammatory pain in the rat. 1628 98


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