Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Side effects of marijuana-based drugs and synthetic analogs of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), including sedation and dysphoria, have limited their therapeutic application. Ajulemic acid (AJA), a side-chain synthetic analog of Delta(8)-THC-11-oic acid, has been reported to have anti-inflammatory properties without producing undesired psychoactive effects. Moreover, it has been suggested that AJA does not interact with cannabinoid receptors to produce its pharmacological effects. The aim of the present study was to conduct a thorough evaluation of the pharmacological effects of AJA then to determine whether actions at cannabinoid receptor (CB)(1) mediated these effects. This study evaluated the psychoactive and analgesic effects of AJA by examining its cannabimimetic properties in ICR mice (i.e., antinociception, catalepsy, hypothermia, and hypomobility), its discriminative stimulus effects in Long Evans rats trained in a two-lever Delta(9)-THC (3.0 mg/kg) versus vehicle drug discrimination procedure, and its antihyperalgesia effects in a rat model of inflammatory pain [complete Freund's adjuvant (CFA)-induced mechanical hyperalgesia]. Lastly, antagonism tests with SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride], CB(1) receptor antagonist, were conducted. These studies demonstrated that AJA shares a number of CB(1)-mediated pharmacological properties with Delta(9)-THC, including cannabimimetic, discriminative stimulus, and antihyperalgesic effects. Furthermore, a separation between doses that produced antinociception and those that produced the other pharmacological effects in mice was not observed. Moreover, AJA showed nearly equipotency for therapeutic efficacy in the CFA model and for substitution in Delta(9)-THC discrimination. In summary, this study shows that AJA, like Delta(9)-THC, exhibits psychoactive and therapeutic effects at nearly equal doses in preclinical models, suggesting similar limitations in their putative therapeutic profiles.
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PMID:Cannabimimetic properties of ajulemic acid. 1710 26

We have shown in past isobolographic studies that a small amount of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) can enhance morphine antinociception in mice. However, previous studies of the Delta(9)-THC/morphine interaction were performed using normal mice or rats and evaluated acute thermal antinociception. Less is known about cannabinoid and opioid interactions involved in mechanical nociception and in chronic inflammatory pain models, such as Freund's complete adjuvant-induced arthritic model. One fixed-ratio combination was chosen for testing the interaction between Delta(9)-THC and morphine in the Freund's adjuvant-induced arthritic model. This combination represented a 1:1 ratio of the drugs and thus consisted of equieffective doses ranging from 0.1 to 5 mg/kg Delta(9)-THC and from 0.1 to 5 mg/kg morphine. The combination ED(50) value for the fixed ratios (total dose) in relation to the ED(50) value of the drugs alone was determined. The isobolographic analysis indicated a synergistic interaction between Delta(9)-THC and morphine in both the non-arthritic and the arthritic rats. Since Freund's adjuvant-induced alteration in endogenous opioid tone has been previously shown, our data indicate that such changes did not preclude the use of Delta(9)-THC and morphine in combination. As with acute preclinical pain models in which the Delta(9)-THC/morphine combination results in less tolerance development, the implication of the study for chronic pain conditions is discussed.
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PMID:Synergy between delta9-tetrahydrocannabinol and morphine in the arthritic rat. 1749 86

Cannabinoid CB(2) receptors have been implicated in antinociception in animal models of both acute and chronic pain. We evaluated the role both cannabinoid CB(1) and CB(2) receptors in mechanonociception in non-arthritic and arthritic rats. The antinociceptive effect of Delta(9)-tetrahydrocannabinol (Delta(9)THC) was determined in rats following administration of the cannabinoid CB(1) receptor-selective antagonist, SR141716A, the cannabinoid CB(2) receptor-selective antagonist, SR144528, or vehicle. Male Sprague-Dawley rats were rendered arthritic using Freund's complete adjuvant and tested for mechanical hyperalgesia in the paw-pressure test. Arthritic rats had a baseline paw-pressure of 83 +/- 3.6 g versus a paw-pressure of 177 +/- 6.42 g in non-arthritic rats. SR144528 or SR141716A (various doses mg/kg; i.p.) or 1:1:18 (ethanol:emulphor:saline) vehicle were injected 1 h prior to Delta(9)THC (4 mg/kg; i.p) or 1:1:18 vehicle and antinociception determined 30min post Delta(9)THC. AD(50)'s for both antagonists were calculated with 95% confidence limits. In addition, midbrain and spinal cord were removed for determination of cannabinoid CB(1) and CB(2) receptor protein density in the rats. SR144528 significantly attenuated the antinociceptive effect of Delta(9)THC in the arthritic rats [AD(50) = 3.3 (2.7-4) mg/kg], but not in the non-arthritic rats at a dose of 10/mg/kg. SR141716A significantly attenuated Delta(9)THC-induced antinociception in both the non-arthritic [AD(50) = 1.4 (0.8-2) mg/kg] and arthritic rat [AD(50) = 2.6 (1.8-3.1) mg/kg]. SR141716A or SR144528 alone did not result in a hyperalgesic effect as compared to vehicle. Our results indicate that the cannabinoid CB(2) receptor plays a critical role in cannabinoid-mediated antinociception, particularly in models of chronic inflammatory pain.
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PMID:The antinociceptive effect of Delta9-tetrahydrocannabinol in the arthritic rat involves the CB(2) cannabinoid receptor. 1758 60

The objective of this study was to review demographic characteristics and drugs detected in carbon monoxide (CO)-related deaths from cases received by the Office of the Cuyahoga County Coroner in Cleveland, Ohio, from 2000-2003. Postmortem reports were reviewed, and decedents for which CO was listed as the cause of death were included. The data were compiled into 3 groups according to the official coroner's verdict as to the manner of death: accident, suicide, and homicide. Included in this study were 122 cases: 84 (69%) accidental, 31 (25%) suicide, and 7 (6%) homicide. Accident decedents were typically white males, aged 40-59 years, residing in Cleveland. Suicide decedents were also middle-aged, white males but residing in the suburbs. Homicide decedents under the age of 6 were characteristically black (N=2), while decedents over the age of 39 were predominately white (N=3). Carboxyhemoglobin (COHb) levels in suicide cases were higher than concentrations measured in accidental deaths. The highest percentage of suicide decedents (36%) had a COHb level>70% saturation, accident decedents (36%) between 50% and 69% saturation, and homicide decedents (71%) below 50% saturation. Ethanol (N=34) was detected in 28% of deaths, and therapeutic and/or abused drugs (N=50) were detected in 41% of deaths. Illicit drugs were detected in 11% of cases (cocaine/metabolites; THC/metabolites), other drug positives were therapeutic medications. The most common drugs detected were antidepressants and antihistamines in suicides and pain medications and antihistamines in accidents.
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PMID:The prevalence of drugs in carbon monoxide-related deaths: a retrospective study, 2000-2003. 1772 Nov 77

Cannabinoids are known to have analgesic properties. We evaluated the effect of oro-mucosal sativex, (THC: CBD), an endocannabinoid system modulator, on pain and allodynia, in 125 patients with neuropathic pain of peripheral origin in a five-week, randomised, double-blind, placebo-controlled, parallel design trial. Patients remained on their existing stable analgesia. A self-titrating regimen was used to optimise drug administration. Sixty-three patients were randomised to receive sativex and 62 placebo. The mean reduction in pain intensity scores (primary outcome measure) was greater in patients receiving sativex than placebo (mean adjusted scores -1.48 points vs. -0.52 points on a 0-10 Numerical Rating Scale (p=0.004; 95% CI: -1.59, -0.32). Improvements in Neuropathic Pain Scale composite score (p=0.007), sleep NRS (p=0.001), dynamic allodynia (p=0.042), punctate allodynia (p=0.021), Pain Disability Index (p=0.003) and Patient's Global Impression of Change (p<0.001) were similarly greater on sativex vs. placebo. Sedative and gastrointestinal side effects were reported more commonly by patients on active medication. Of all participants, 18% on sativex and 3% on placebo withdrew during the study. An open-label extension study showed that the initial pain relief was maintained without dose escalation or toxicity for 52 weeks.
Pain 2007 Dec 15
PMID:Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. 1799 24

We have previously demonstrated synergy between morphine and Delta(9)-tetrahydrocannabinol (Delta(9)-THC) in the expression of antinociception in acute pain models and in arthritic models of chronic pain. Our data has been extended to include acute pain in both diabetic mice and rats. In diabetic mice, Delta(9)-THC p.o. was more active in the tail-flick test in the diabetic mouse than in the non-diabetic mouse. Morphine (s.c.) was less potent in diabetic than in non-diabetic mice [6.1 (5.1-7.2) versus 3.2 (2.4-4.1) mg/kg, respectively], an effect previously extensively documented in pre-clinical and clinical testing. In addition, the combination of Delta(9)-THC with morphine produced a greater-than-additive relief of acute pain in mice. In the rat, the induction of the diabetic state decreased the antinociceptive effect of morphine, an effect temporally related to a decreased release of specific endogenous opioids. Conversely, Delta(9)-THC retained the ability to release endogenous opioids in diabetic rats and maintained significant antinociception. Extrapolation of such studies to the clinical setting may indicate the potential for use of Delta(9)-THC-like drugs in the treatment of diabetic neuropathic pain, alone or in combination with very low doses of opioids.
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PMID:Decreased basal endogenous opioid levels in diabetic rodents: effects on morphine and delta-9-tetrahydrocannabinoid-induced antinociception. 1831 63

During the 1990s, transmembranal proteins in the central nervous system (CNS) that recognize the principal compound of marijuana, the delta-9-tetrahydrocannabinol (Delta9-THC) were described. The receptors were classified as central or peripheral, CB1 and CB2, respectively. To this date, it has been documented the presence in the CNS of specific lipids that bind naturally to the CB1/CB2 receptors. The family of endogenous cannabinoids or endocannabinoids comprises oleamide, arachidonoylethanolamine, 2-arachidonylglycerol, virodhamine, noladin ether and N-arachidonyldopamine. Pharmacological experiments have shown that those compounds induce cannabimimetic effects. Endocannabinoids are fatty acid derivates that have a variety of biological actions, most notably via activation of the cannabinoid receptors. The endocannabinoids have an active role modulating diverse neurobiological functions, such as learning and memory, feeding, pain perception and sleep generation. Experimental evidence shows that the administration of Delta9-THC promotes sleep. The activation of the CB1 receptor leads to an induction of sleep, this effect is blocked via the selective antagonist. Since the system of the endogenous cannabinoids is present in several species, including humans, this leads to the speculation of the neurobiological role of the endocannabinoid system on diverse functions such as sleep modulation. This review discusses the evidence of the system of the endocannabinoids as well as their physiological role in diverse behaviours, including the modulation of sleep.
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PMID:The role of the CB1 receptor in the regulation of sleep. 1851 75

Advances in cannabis research have paralleled developments in opioid pharmacology whereby a psychoactive plant extract has elucidated novel endogenous signalling systems with therapeutic significance. Cannabinoids (CBs) are chemical compounds derived from cannabis. The major psychotropic CB delta-9-tetrahydrocannabinol (Delta(9)-THC) was isolated in 1964 and the first CB receptor (CB(1)R) was cloned in 1990. CB signalling occurs via G-protein-coupled receptors distributed throughout the body. Endocannabinoids are derivatives of arachidonic acid that function in diverse physiological systems. Neuronal CB(1)Rs modulate synaptic transmission and mediate psychoactivity. Immune-cell CB(2) receptors (CB(2)R) may down-regulate neuroinflammation and influence cyclooxygenase-dependent pathways. Animal models demonstrate that CBRs play a fundamental role in peripheral, spinal, and supraspinal nociception and that CBs are effective analgesics. Clinical trials of CBs in multiple sclerosis have suggested a benefit in neuropathic pain. However, human studies of CB-mediated analgesia have been limited by study size, heterogeneous patient populations, and subjective outcome measures. Furthermore, CBs have variable pharmacokinetics and can manifest psychotropism. They are currently licensed as antiemetics in chemotherapy and can be prescribed on a named-patient basis for neuropathic pain. Future selective peripheral CB(1)R and CB(2)R agonists will minimize central psychoactivity and may synergize opioid anti-nociception. This review discusses the basic science and clinical aspects of CB pharmacology with a focus on pain medicine.
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PMID:Therapeutic potential of cannabis in pain medicine. 1851 70

This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing cannabinoids in pain treatment. Tetrahydrocannabinol (THC, Marinol((R))) and nabilone (Cesamet((R))) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation. Sativex((R)), a cannabis derived oromucosal spray containing equal proportions of THC (partial CB(1) receptor agonist ) and cannabidiol (CBD, a non-euphoriant, anti-inflammatory analgesic with CB(1) receptor antagonist and endocannabinoid modulating effects) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis, and in 2007 for intractable cancer pain. Numerous randomized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain. An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006. Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles. Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise.
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PMID:Cannabinoids in the management of difficult to treat pain. 1872 14

THE OBJECTIVE OF THIS STUDY WAS TO COMPARE THE EFFECTIVENESS OF TWO COMPILED PHYSIOTHERAPY PROGRAMS: one including forceful traction mobilizations, the other including traction with unknown force, in patients with hip disability according to ICF (the International Classification of Functioning, Disability and Health, 2001; WHO), using a block randomized, controlled trial with two parallel treatment groups in a regular private outpatient physiotherapy practice. In the experimental group (E; n = 10) and control group (C; n = 9), the mean (+/-SD) age for all participants was 59 +/- 12 years. They were recruited from outpatient physiotherapy clinics, had persistent pain located at the hip joint for >8 weeks and hip hypomobility. Both groups received exercise, information and manual traction mobilization. In E, the traction force was progressed to 800 N, whereas in C it was unknown. Major outcome measure was the median total change score >/=20 points or >/=50% of the disease- and joint-specific Hip disability and Osteoarthritis Outcome Score (HOOS), compiled of Pain, Stiffness, Function and Hip-related quality of life (ranging 0-100). The mean (range) treatments received were 13 (7-16) over 5-12 weeks and 20 (18-24) over 12 weeks for E and C, respectively. The experimental group showed superior clinical post-treatment effect on HOOS (>/=20 points), in six of 10 participants compared with none of nine in the control group (p = 0.011). The effect size was 1.1. The results suggest that a compiled physiotherapy program including forceful traction mobilizations are short-term effective in reducing self-rated hip disability in primary healthcare. The long-term effect is to be documented.
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PMID:Superior effect of forceful compared with standard traction mobilizations in hip disability? 1883 35


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