UMLS:C0344307 - FACTA Search

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Query: UMLS:C0344307 (analgesia)
28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two subtypes of cannabinoid receptors have been identified to date, the CB1 receptor, essentially located in the CNS, but also in peripheral tissues, and the CB2 receptor, found only at the periphery. The identification of delta9-tetrahydrocannabinol (delta9-THC) as the major active component of marijuana (Cannabis sativa), the recent emergence of potent synthetic ligands and the identification of anandamide and sn-2 arachidonylglycerol as putative endogenous ligands for cannabinoid receptors in the brain, have contributed to advancing cannabinoid pharmacology and approaching the neurobiological mechanisms involved in physiological and behavioral effects of cannabinoids. Most of the agonists exhibit nonselective affinity for CB1/CB2 receptors, and delta9-THC and anandamide probably act as partial agonists. Some recently synthesized molecules are highly selective for CB2 receptors, whereas selective agonists for the CB1 receptors are not yet available. A small number of antagonists exist that display a high selectivity for either CB1 or CB2 receptors. Cannabinomimetics produce complex pharmacological and behavioral effects that probably involve numerous neuronal substrates. Interactions with dopamine, acetylcholine, opiate, and GABAergic systems have been demonstrated in several brain structures. In animals, cannabinoid agonists such as delta9-THC, WIN 55,212-2, and CP 55,940 produce a characteristic combination of four symptoms, hypothermia, analgesia, hypoactivity, and catalepsy. They are reversed by the selective CB1 receptor antagonist, SR 141716, providing good evidence for the involvement of CB1-related mechanisms. Anandamide exhibits several differences, compared with other agonists. In particular, hypothermia, analgesia, and catalepsy induced by this endogenous ligand are not reversed by SR 141716. Cannabinoid-related processes seem also involved in cognition, memory, anxiety, control of appetite, emesis, inflammatory, and immune responses. Agonists may induce biphasic effects, for example, hyperactivity at low doses and severe motor deficits at larger doses. Intriguingly, although cannabis is widely used as recreational drug in humans, only a few studies revealed an appetitive potential of cannabimimetics in animals, and evidence for aversive effects of delta9-THC, WIN 55,212-2, and CP 55,940 is more readily obtained in a variety of tests. The selective blockade of CB1 receptors by SR 141716 impaired the perception of the appetitive value of positive reinforcers (food, cocaine, morphine) and reduced the motivation for sucrose, beer and alcohol consumption, indicating that positive incentive and/or motivational processes could be under a permissive control of CB1-related mechanisms. There is little evidence that cannabinoid systems are activated under basal conditions. However, by using SR 141716 as a tool, a tonic involvement of a CB1-mediated cannabinoid link has been demonstrated, notably in animals suffering from chronic pain, faced with anxiogenic stimuli or highly motivational reinforcers. Some effects of SR 141716 also suggest that CB1-related mechanisms exert a tonic control on cognitive processes. Extensive basic research is still needed to elucidate the roles of cannabinoid systems, both in the brain and at the periphery, in normal physiology and in diseases. Additional compounds, such as selective CB1 receptor agonists, ligands that do not cross the blood brain barrier, drugs interfering with synthesis, degradation or uptake of endogenous ligand(s) of CB receptors, are especially needed to understand when and how cannabinoid systems are activated. In turn, new therapeutic strategies would likely to emerge.
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PMID:Behavioral effects of cannabinoid agents in animals. 1080 37

Cannabinoids which impair rat working memory appear to inhibit hippocampal extracellular acetylcholine (Ach) release and reduce choline uptake through an interaction with CB1 cannabinoid receptors. Here we report that CP 55,940, a potent bicyclic synthetic cannabinoid analog, dose-dependently impaired rat performance, when given i.p. 20 min before an eight-arm radial maze test. The selective CB1 cannabinoid receptor antagonist SR 141716A, given i.p. 20 min earlier, significantly reduced the memory deficit Pretreatment with eptastigmine, a second generation cholinesterase inhibitor, given orally 100 min before the cannabinoid agonist, relieved the memory impairment without affecting CP 55,940-induced behavioural alterations such as reduced spontaneous motor activity, analgesia and hind limb splaying. These data suggest that cannabinoid-induced working memory impairment is mediated through a central cholinergic blockade.
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PMID:Cannabinoid-induced working memory impairment is reversed by a second generation cholinesterase inhibitor in rats. 1088 65

Understanding of cannabinoid (CB) actions has been remarkably advanced during the last decade, due mainly to the identification of the G-protein-coupled cannabinoid receptors, namely, CB1 receptors that are predominantly found in the brain and CB2 receptors that are exclusively found in peripheral tissues. Endogenous ligands for these receptors have also been identified. Research to date suggests that the analgesic effect of cannabinoids and the enhancement of opioid analgesia by cannabinoids are both CB1 receptor-mediated via the activation of opioid receptors. The involvement of the CB1 receptor in mediating reinforcing and physical dependence-producing effects of opioids has also been suggested, with the former being considered the result of interaction with the dopaminergic neurotransmission in the midbrain dopamine system. However, the discriminative stimulus effects of cannabinoids have been reported to be highly specific in that the effects were not substituted by other classes of compounds including opioidergic and dopaminergic agents nor were they antagonized by antagonists of various neurotransmission systems, suggesting that the discriminative stimulus effects only involve the cannabinoid system. Thus the cannabinoid actions appear to be classifiable into at least two kinds: 1) those mediated directly through cannabinoid receptors and 2) those mediated indirectly through other systems such as opioidergic systems. Detailed research into these actions may help to elucidate not only the mechanisms of action of exogenous cannabinoids but also the role of endogenous cannabinoids, especially in the brain reward system.
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PMID:Role of cannabinoid receptor in the brain as it relates to drug reward. 1113 22

The purpose of this study was to evaluate the possible contribution of metabotropic glutamate receptors (mGluRs) to cannabinoid-induced antinociception in the periaqueductal grey (PAG) matter of rats. Intra-PAG microinjection of WIN 55,212-2, a cannabinoid receptor agonist, increased the latency of the nociceptive reaction (NR) in a dose-dependent fashion in the plantar test. This effect was prevented by pretreatment with SR141716A, a selective antagonist of CB1 receptors. When injected alone, SR141716A produced, with the highest dosage used, a significant reduction in the latency of the NR. CPCCOEt, a selective mGlu1 receptor antagonist, was unable to prevent the analgesia produced by WIN 55,212-2. On the contrary, MPEP, a selective mGlu5 receptor antagonist, completely antagonized the effect of WIN 55,212-2. However, the analgesia induced by CHPG, a selective mGlu5 receptor agonist, was blocked by MPEP but not by SR141716A. When injected alone, CPCOOEt produced no effect, whereas MPEP produced, with the highest dosage used, a significant reduction in the latency of the NR. These data emphasize that mGlu5 receptors, but not mGluR1, may modulate nociception in the PAG. Similarly, a pretreatment with either 2-(S)-alpha-EGlu or (RS)-alpha-MSOP, selective antagonists for group II and III mGluRs, respectively, prevented the WIN 55,212-2-induced analgesia. When the higher dosage of (RS)-alpha-MSOP was used a decrease in the latency of the NR was observed. This was not the case for 2-(S)-alpha-EGlu. Pretreatment with DL-AP5, a selective antagonist of N-methyl-D-aspartate (NMDA) receptors, blocked the effect of WIN 55,212-2, and by increasing the dosage strongly reduced per se the latency of the NR. This study suggests that endogenous glutamate could tonically modulate nociception through mGlu and NMDA receptors in the PAG matter. In particular, the physiological stimulation of these receptors seems to be required for the cannabinoid-induced analgesia in this midbrain area.
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PMID:Metabotropic and NMDA glutamate receptors participate in the cannabinoid-induced antinociception. 1116 24

Cannabinoids are known to suppress responses to noxious stimulation in animals and man. Recent research has suggested a role for endogenous cannabinoids in the descending inhibition of dorsal horn cells via a supraspinal site of action. We have recently demonstrated [J. Physiol. 506(2) (1998) 459] that the nucleus reticularis gigantocellularis pars alpha (GiA) is a major source of such descending modulation, and importantly, that this system is activated in response to noxious stimulation. We have therefore investigated the role of CB1 receptor activation in mediating the antinociceptive effects of activation of GiA in models of acute and chronic pain. Microinjections (0.5 microl 60% DMSO) of either WIN 55,212-2 (5 microg, selective CB1 agonist), SR141716A (50 microg, competitive CB1 antagonist), both compounds together, or vehicle alone into GiA were performed prior to these tests in a randomised, blind manner. In control animals, WIN 55,212-2 markedly increased withdrawal latencies in the tail flick test and reduced responses to subcutaneous formalin. These effects were blocked by co-administration of SR141716A. These data suggest that activation of cannabinoid CB1 receptor subtypes in GiA leads to behavioural analgesia. In animals with partial sciatic nerve ligation, microinjection of drugs and injection of formalin were performed contralaterally to the site of ligation. Partial sciatic nerve ligation significantly reduced behavioural responses to contralaterally applied formalin. Microinjection of SR141716A to GiA reversed this inhibition of responses to formalin in animals with partial sciatic nerve ligation. These data provide evidence that endogenous CB1 receptor ligands are involved in GiA mediated antinociception, and that this system is important for the modulation of nociceptive transmission in an animal model of chronic neuropathic pain.
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PMID:CB1 receptor mediated analgesia from the Nucleus Reticularis Gigantocellularis pars alpha is activated in an animal model of neuropathic pain. 1145 32

The role of cannabinoids in spinal analgesia has so far been investigated in mammals and the interactions between cannabinoid receptors and markers involved in nociception have been described in the rat spinal cord. An endocannabinoid system is well developed also in the amphibian brain. However, the anatomical substrates of pain modulation have been scarcely investigated in anamniotes, neither is there reference to such a role for cannabinoids in lower vertebrates. In the present paper we employed multiple cytochemical approaches to study the distribution of CB1 cannabinoid receptors and their morphofunctional relationships with some nociception markers (i.e. Substance P, nitric oxide synthase, GABA and mu opioid receptors) in the spinal cord of the anuran amphibian Xenopus laevis. We found a co-distribution of CB1 receptors with the aforementioned signaling molecules, as well as a more limited cellular co-localization, in the dorsal and central fields of the spinal cord. These regions correspond to the mammalian laminae I-IV and X, respectively, areas strongly involved in spinal analgesia. Comparison of these results with those previously obtained in the mammalian spinal cord, reveals a number of similarities between the two systems and suggests that cannabinoids might participate in the control of pain sensitivity also in the amphibian spinal cord.
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PMID:CB1 cannabinoid receptors in amphibian spinal cord: relationships with some nociception markers. 1229 61

Cannabinoids act at receptors on peripheral and central neurons to modulate diverse physiological functions and produce analgesia. Corneal sensory nerves express the CB1 cannabinoid receptor and project to two spatially discrete regions of the lower brainstem, the trigeminal interpolaris/caudalis (Vi/Vc) transition and subnucleus caudalis/upper cervical cord (Vc/C1) junction region. The function of CB1 expression on corneal nerves is not known. To determine if cannabinoid receptors in the anterior eye affect the activity of trigeminal brainstem neurons at the Vi/Vc and Vc/C1 the CB1 agonist, WIN55,212-2 (WIN-2), was applied topically prior to chemical excitation of corneal afferent fibers. In the first series of experiments WIN-2 was applied topically prior to excitation of corneal nociceptors by mustard oil (MO). WIN-2 reduced significantly the number of Fos-like immunoreactive neuronal nuclei (Fos-LI) at the Vi/Vc transition (-46.7+/-8.2%, P<0.05), while smaller non-significant reductions occurred at the Vc/C1 junction region (-20.3+/-7.6%). The selective CB1 antagonist, SR141716A (1mg/kg, i.v.), prevented WIN-2-evoked reduction in Fos-LI after MO. Systemic administration of WIN-2 (1 or 10mg/kg, i.p.) or SR141716A (1mg/kg, i.v.) or topical corneal application of morphine sulfate did not affect Fos-LI produced by MO. In parallel experiments, topical WIN-2 reduced the magnitude of single unit activity recorded at the Vi/Vc transition (-80+/-7%, P<0.025), but not at the Vc/C1 junction region (-34+/-30%) evoked by CO(2) pulses applied to the cornea. Topical morphine did not alter CO(2)-evoked unit activity at either recording location. These results indicated that cannabinoid receptor agonists acted, at least in part, at CB1 receptors in the anterior eye to reduce corneal stimulation-evoked trigeminal brainstem neural activity. Corneal nociceptor-evoked activity at the Vi/Vc transition was reduced significantly by topical WIN-2, while activity at the Vc/C1 junction region displayed only minor decreases. These findings were consistent with the hypothesis that CB1 receptors affect the activity of corneal-responsive neurons that preferentially contribute to homeostasis of the anterior eye and/or reflexive aspects of nociception rather than the sensory-discriminative aspects of corneal nociception.
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PMID:Topical cannabinoid agonist, WIN55,212-2, reduces cornea-evoked trigeminal brainstem activity in the rat. 1240 31

Cannabis occurs naturally in the dried flowering or fruiting tops of the Cannabis sativa plant. Cannabis is most often consumed by smoking marihuana. Cannabinoids are the active compounds extracted from cannabis. Recently, there has been renewed interest in cannabinoids for medicinal purposes. The two proven indications for the use of the synthetic cannabinoid (dronabinol) are chemotherapy-induced nausea and vomiting and AIDS-related anorexia. Other possible effects that may prove beneficial in the oncology population include analgesia, antitumor effect, mood elevation, muscle relaxation, and relief of insomnia. Two types of cannabinoid receptors, CB1 and CB2, have been detected. CB1 receptors are expressed mainly in the central and peripheral nervous system. CB2 receptors are found in certain nonneuronal tissues, particularly in the immune cells. Recent discovery of both the cannabinoid receptors and endocannabinoids has opened a new era in research on the pharmaceutical applications of cannabinoids. The use of cannabinoids should be continued in the areas indicated, and further studies are needed to evaluate other potential uses in clinical oncology.
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PMID:Established and potential therapeutic applications of cannabinoids in oncology. 1261 20

In the rat, antinociception of supraspinal origin is observed in response to administration of cocaine or an antagonist of the NMDA receptor for glutamate. The current study was conducted to determine if endocannabinoids are involved in the antinociceptive effect of cocaine, or antagonism of NMDA receptor binding. Intraperitoneal (i.p.) administration to male rats of cocaine, or the NMDA receptor antagonist, MK-801, resulted in a significant antinociceptive response of supraspinal origin, as indicated by a significant increase in reaction time in the hot plate test of analgesia (increase in the amount of time before the animal reacted to the hot plate by licking its paws or jumping). Treatment with SR141716A, a specific antagonist of the cannabinoid (CB1) receptor, resulted in a complete reversal of cocaine-induced antinociception when administered at a dose of 5.0mg/kg. Although the 2.5 and 5.0mg/kg doses of SR141716A produced a significant reduction in the antinociceptive effect of MK-801, the effect was incomplete since the reaction time in the hot plate test remained greater than that observed in vehicle-treated controls. These findings suggest that activation of the CB1 receptor participates significantly in antinociception resulting from treatment with cocaine and with the NMDA receptor antagonist, MK-801. The partial reversal of the antinociceptive effect of MK-801 by CB1 receptor antagonism indicates other mediators of nociception, in addition to the endocannabinoids, appear to be active in the antinociceptive response to NMDA receptor antagonism.
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PMID:The effect of cannabinoid receptor antagonism with SR141716A on antinociception induced by cocaine and the NMDA receptor antagonist, MK-801. 1283 1

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.
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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

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