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

Cannabinoids and opioids are distinct drug classes historically used in combination to treat pain. Delta(9)-THC, an active constituent in marijuana, releases endogenous dynorphin A and leucine enkephalin in the production of analgesia. The endocannabinoid, anandamide (AEA), fails to release dynorphin A. The synthetic cannabinoid, CP55,940, releases dynorphin B. Neither AEA nor CP55,940 enhances morphine analgesia. The CB1 antagonist, SR141716A, differentially blocks Delta(9)-THC versus AEA. Tolerance to Delta(9)-THC, but not AEA, involves a decrease in the release of dynorphin A. Our preclinical studies indicate that Delta(9)-THC and morphine can be useful in low dose combination as an analgesic. Such is not observed with AEA or CP55,940. We hypothesize the existence of a new CB receptor differentially linked to endogenous opioid systems based upon data showing the stereoselectivity of endogenous opioid release. Such a receptor, due to the release of endogenous opioids, may have significant impact upon the clinical development of cannabinoid/opioid combinations for the treatment of a variety of types of pain in humans.
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PMID:Synergistic interactions of endogenous opioids and cannabinoid systems. 1061 10

A common obstacle in clinical management of pathological pain is the poor response to opioid analgesics. We now report that delta9-tetrahydrocannabinol (delta9-THC)-induced antinociception remained effective in rats with pathological pain. The selective central cannabinoid receptor antagonist SR141716A, but not the generic opioid receptor antagonist naloxone, blocked the delta9-THC antinociception. Moreover, there is no cross-tolerance between the antinociceptive effects of morphine and delta9-THC in pathological pain states. The results indicate that delta9-THC antinociception is both effective and independent of opioid receptors in rats with pathological pain. Thus, the cannabinoid analgesic system may be superior to opioids in alleviating intractable pathological pain syndromes.
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PMID:Two distinctive antinociceptive systems in rats with pathological pain. 1069

Perinatal Delta(9)-tetrahydrocannabinol (Delta(9)-THC) exposure in rats resulted in enhanced morphine self-administration behavior, naloxone-precipitated withdrawal signs or changes in pain sensitivity, which have been related to changes in micro-opioid receptor binding and/or proenkephalin mRNA levels in several brain regions. However, despite exposure of these animals to Delta(9)-THC from fetal ages, the effects were studied only when animals matured, whereas there is no study on possible changes caused by this cannabinoid during the prenatal ontogeny of opioidergic neurons. The purpose of the present study was to examine the changes in proenkephalin mRNA levels, measured by using in situ hybridization, in several brain nuclei of rat fetuses that had been daily exposed to Delta(9)-THC from the 5th day of gestation. Results were as follows. Prenatal Delta(9)-THC exposure altered proenkephalin mRNA levels in most of the brain areas studied at different fetal ages, but the effects were different between sexes. Thus, proenkephalin mRNA levels increased in females, but decreased in males that had been prenatally exposed to Delta(9)-THC. This was observed in the caudate-putamen, hypothalamic paraventricular and ventromedial nuclei and cerebral cortex. No changes were observed, however, in the subventricular zones of the caudate-putamen, neocortex and nucleus accumbens. In summary, prenatal Delta(9)-THC exposure produced a sex-dependent effect in proenkephalin mRNA levels in several brain structures of rat fetuses.
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PMID:Prenatal Delta(9)-tetrahydrocannabinol exposure modifies proenkephalin gene expression in the fetal rat brain: sex-dependent differences. 1072 32

Cannabis has a potential for clinical use often obscured by unreliable and purely anecdotal reports. The most important natural cannabinoid is the psychoactive tetrahydrocannabinol (delta9-THC); others include cannabidiol (CBD) and cannabigerol (CBG). Not all the observed effects can be ascribed to THC, and the other constituents may also modulate its action; for example CBD reduces anxiety induced by THC. A standardised extract of the herb may be therefore be more beneficial in practice and clinical trial protocols have been drawn up to assess this. The mechanism of action is still not fully understood, although cannabinoid receptors have been cloned and natural ligands identified. Cannabis is frequently used by patients with multiple sclerosis (MS) for muscle spasm and pain, and in an experimental model of MS low doses of cannabinoids alleviated tremor. Most of the controlled studies have been carried out with THC rather than cannabis herb and so do not mimic the usual clincal situation. Small clinical studies have confirmed the usefulness of THC as an analgesic; CBD and CBG also have analgesic and antiinflammatory effects, indicating that there is scope for developing drugs which do not have the psychoactive properties of THC. Patients taking the synthetic derivative nabilone for neurogenic pain actually preferred cannabis herb and reported that it relieved not only pain but the associated depression and anxiety. Cannabinoids are effective in chemotherapy-induced emesis and nabilone has been licensed for this use for several years. Currently, the synthetic cannabinoid HU211 is undergoing trials as a protective agent after brain trauma. Anecdotal reports of cannabis use include case studies in migraine and Tourette's syndrome, and as a treatment for asthma and glaucoma. Apart from the smoking aspect, the safety profile of cannabis is fairly good. However, adverse reactions include panic or anxiety attacks, which are worse in the elderly and in women, and less likely in children. Although psychosis has been cited as a consequence of cannabis use, an examination of psychiatric hospital admissions found no evidence of this, however, it may exacerbate existing symptoms. The relatively slow elimination from the body of the cannabinoids has safety implications for cognitive tasks, especially driving and operating machinery; although driving impairment with cannabis is only moderate, there is a significant interaction with alcohol. Natural materials are highly variable and multiple components need to be standardised to ensure reproducible effects. Pure natural and synthetic compounds do not have these disadvantages but may not have the overall therapeutic effect of the herb.
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PMID:Cannabinoids in clinical practice. 1115 13

Nephrolithiasis is one of the most common diseases in the Western world. The disease manifests itself with intensive pain, sporadic infections, and, sometimes, renal failure. The symptoms are due to the appearance of urinary stones (calculi) which are formed mainly by calcium salts. These calcium salts precipitate in the renal papillae and/or within the collecting ducts. Inherited forms of nephrolithiasis related to chromosome X (X-linked hypercalciuric nephrolithiasis or XLN) have been recently described. Hypercalciuria, nephrocalcinosis, and male predominance are the major characteristics of these diseases. The gene responsible for the XLN forms of kidney stones was cloned and characterized as a chloride channel called ClC-5. The ClC-5 chloride channel belongs to a superfamily of voltage-gated chloride channels, whose physiological roles are not completely understood. The objective of the present review is to identify recent advances in the molecular pathology of nephrolithiasis, with emphasis on XLN. We also try to establish a link between a chloride channel like ClC-5, hypercalciuria, failure in urine acidification and protein endocytosis, which could explain the symptoms exhibited by XLN patients.
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PMID:ClC-5 chloride channel and kidney stones: what is the link? 1126 81

There is a large amount of evidence to support the view that the psychoactive ingredient in cannabis, delta9-tetrahydrocannabinol (delta9-THC), and cannabinoids in general, can reduce muscle spasticity and pain under some circumstances. Cannabinoid (CB1) receptors in the CNS appear to mediate both of these effects and endogenous cannabinoids may fulfil these functions to some extent under normal circumstances. However, in the context of multiple sclerosis (MS), it is still questionable whether cannabinoids are superior to existing, conventional medicationsfor the treatment of spasticity and pain. In the case of spasticity, there are too few controlled clinical trials to draw any reliable conclusion at this stage. In the case of pain, most of the available trials suggest that cannabinoids are not superior to existing treatments; however, few trials have examined chronic pain syndromes that are relevant to MS. Whether or not cannabinoids do have therapeutic potential in the treatment of MS, a further issue will be whether synthetic cannabinoids should be used in preference to cannabis itself. Smoking cannabis is associated with significant risks of lung cancer and other respiratory dysfunction. Furthermore, delta9-THC, as a broad-spectrum cannabinoid receptor agonist, will activate both CB1 and CB2 receptors. Synthetic cannabinoids, which target specific cannabinoid receptor subtypes in specific parts of the CNS, are likely to be of more therapeutic use than delta9-THC itself. If rapid absorption is necessary, such synthetic drugs could be delivered via aerosol formulations.
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PMID:Cannabinoids in the treatment of pain and spasticity in multiple sclerosis. 1213 4

Spinal antinociception produced by delta 9-tetrahydro-cannabinol (Delta(9)-THC) and other cannabinoid agonists has been suggested to be mediated by the release of dynorphin acting at the kappa opioid receptor. Alternatively, as cannabinoid receptors are distributed appropriately in the pain transmission pathway, cannabinoid agonists might act directly at the spinal level to inhibit nociception, without requiring dynorphin release. Here, these possibilities were explored using mice with a deletion of the gene encoding prodynorphin. Antinociceptive dose-response curves were constructed for spinal Delta(9)-THC and WIN 55,212-2 in prodynorphin knock-out mice and in wild-type littermates. WIN 55,212-2 and Delta(9)-THC were equipotent in the wild-type and prodynorphin knock-out mice. Spinal pretreatment with a kappa opioid receptor antagonist, nor-binaltorphimine (nor-BNI), did not alter the dose-response curves for either WIN 55,212-2 or Delta(9)-THC in prodynorphin knock-out and wild-type mice. However, the same dose of nor-BNI used blocked U50,488H-induced antinociception in both wild-type and prodynorphin knock-out mice, confirming kappa opioid receptor activity. Pretreatment with SR141716A, a cannabinoid receptor antagonist blocked the antinociceptive actions of both WIN 55,212-2 and Delta(9)-THC. These data support the conclusion that antinociception produced by spinal cannabinoids are likely to be mediated directly through activation of cannabinoid receptors without the requirement for dynorphin release or activation of kappa opioid receptors.
Pain 2002 Dec
PMID:Dynorphin-independent spinal cannabinoid antinociception. 1246 95

The analgesic effects of opioids, such as morphine and codeine, in mice are enhanced by oral administration of the cannabinoid delta(9)-tetrahydrocannabinol (delta(9)-THC). However, isobolographic analysis has never been done to confirm a synergy between delta(9)-THC and morphine or codeine via oral routes of administration. To determine the nature of the interaction between these drugs for pain relief and extend previous experimental results, we performed an isobolographic analysis to evaluate for additivity or synergy in the tail-flick test. Fixed-ratio combinations of delta(9)-THC with either morphine or codeine were tested for antinociceptive effects. The experimentally derived ED(50) for each combination was compared with the theoretical additive ED(50), using an isobolographic analysis. All of the fixed-ratio combinations tested produced greater antinociception (synergy) than predicted from simple additivity. These findings suggest that the use of a low-dose combination of analgesics is a valid and effective approach for the treatment of pain and necessitates further study.
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PMID:Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. 1260 76

The major psychoactive constituent of Cannabis sativa, delta(9)-tetrahydrocannabinol (delta(9)-THC), and endogenous cannabinoid ligands, such as anandamide, signal through G-protein-coupled cannabinoid receptors localised to regions of the brain associated with important neurological processes. Signalling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in CNS disease where inhibition of neurotransmitter release would be beneficial. Anecdotal evidence suggests that patients with disorders such as multiple sclerosis smoke cannabis to relieve disease-related symptoms. Cannabinoids can alleviate tremor and spasticity in animal models of multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress. The cannabinoid nabilone is currently licensed for use as an antiemetic agent in chemotherapy-induced emesis. Evidence suggests that cannabinoids may prove useful in Parkinson's disease by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor suggests that they may be potent neuroprotective agents. Dexanabinol (HU-211), a synthetic cannabinoid, is currently being assessed in clinical trials for traumatic brain injury and stroke. Animal models of mechanical, thermal and noxious pain suggest that cannabinoids may be effective analgesics. Indeed, in clinical trials of postoperative and cancer pain and pain associated with spinal cord injury, cannabinoids have proven more effective than placebo but may be less effective than existing therapies. Dronabinol, a commercially available form of delta(9)-THC, has been used successfully for increasing appetite in patients with HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity. Acute adverse effects following cannabis usage include sedation and anxiety. These effects are usually transient and may be less severe than those that occur with existing therapeutic agents. The use of nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits. The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB(1) receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB(1) receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the endocannabinoid system may also reduce adverse effects and increase the efficacy of cannabinoid treatment. This review highlights recent advances in understanding of the endocannabinoid system and indicates CNS disorders that may benefit from the therapeutic effects of cannabinoid treatment. Where applicable, reference is made to ongoing clinical trials of cannabinoids to alleviate symptoms of these disorders.
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PMID:Therapeutic potential of cannabinoids in CNS disease. 1261 97

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


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