Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cannabinoid Receptor Modulators”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,387 records · Page 77Linked to original sources
PubMed2002

Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors.

Repeated THC administration produces motivational and somatic adaptive changes leading to dependence in rodents. To investigate the molecular basis for cannabinoid dependence and its possible relationship with the endogenous opioid system, we explored delta9-tetrahydrocannabinol (THC) activity in mice lacking mu-, delta- or kappa-opioid receptor genes. Acute THC-induced hypothermia, antinociception, and hypolocomotion remained unaffected in these mice, whereas THC tolerance and withdrawal were minimally modified in mutant animals. In contrast, profound phenotypic changes are observed in several place conditioning protocols that reveal both THC rewarding and aversive properties. Absence of microreceptors abolishes THC place preference. Deletion of kappa receptors ablates THC place aversion and furthermore unmasks THC place preference. Thus, an opposing activity of mu- and kappa-opioid receptors in modulating reward pathways forms the basis for the dual euphoric-dysphoric activity of THC.

Analysis of Variance↗
PubMed2001

Endogenous cannabinoid as a retrograde messenger from depolarized postsynaptic neurons to presynaptic terminals.

Cannabinoid receptors are the molecular targets for the active component Delta(9)-tetrahydrocannabinol of marijuana and hashish, and constitute a major family of G protein-coupled seven-transmembrane-domain receptors. They consist of type 1 (CB1) and type 2 (CB2) receptors of which the CB1 is rich in various regions of the CNS. Accumulated evidence suggests that endogenous cannabinoids function as diffusible and short-lived intercellular messengers that modulate synaptic transmission. Recent studies have provided strong experimental evidence that endogenous cannabinoids mediate signals retrogradely from depolarized postsynaptic neurons to presynaptic terminals to suppress subsequent neurotransmitter release, driving the synapse into an altered state. In hippocampal neurons, depolarization of postsynaptic neurons and resultant elevation of [Ca(2+)](i) lead to transient suppression of inhibitory transmitter release (depolarization-induced suppression of inhibition, DSI). In cerebellar Purkinje cells, on the other hand, depolarization-induced elevation of [Ca(2+)](i) causes transient suppression of excitatory transmitter release (depolarization-induced suppression of excitation, DSE). DSI and DSE appear to share the same properties and may be a general and important mechanism by which the postsynaptic neuronal activity can influence the amount of transmitter release.

Animals↗
PubMed2004

Trends in the development of new antidepressants. Is there a light at the end of the tunnel?

Since the introduction of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) in mid-1950's, treatment of depression has been dominated by monoamine hypotheses. The well-established clinical efficacy of TCAs and MAOIs is due, at least in part, to the enhancement of noradrenergic or serotonergic mechanisms, or to both. Unfortunately, their very broad mechanisms of action also include many unwanted effects related to their potent activity on cholinergic, adrenergic and histaminergic receptors. The introduction of selective serotonin reuptake inhibitors (SSRIs) over twenty years ago had been the next major step in the evolution of antidepressants to develop drugs as effective as the TCAs but of higher safety and tolerability profile. During the past two decades SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) gained incredible popularity and have become the most widely prescribed medication in the psychiatric practice. The evolution of antidepressants continued resulting in introduction of selective and reversible monoamine oxidase inhibitors (eg. moclobemid), selective noradrenaline (eg. reboxetine), dual noradrenaline and serotonin reuptake inhibitors (milnacipram, venlafaxin, duloxetin) and drugs with distinct neurochemical profiles such as mirtazapine, nefazadone and tianeptine. Different novel serotonin receptor ligands have also been intensively investigated. In spite of the remarkable structural diversity, most currently introduced antidepressants are 'monoamine based'. Furthermore, these newer agents are neither more efficacious nor rapid acting than their predecessors and approximately 30% of the population do not respond to current therapies. By the turn of the new millennium, we are all witnessing a result of innovative developmental strategies based on the better understanding of pathophysiology of depressive disorder. Several truly novel concepts have emerged suggesting that the modulation of neuropeptide (substance P, corticotrophin-releasing factor, neuropeptide Y, vasopressin V1b, melanin-concentrating hormone-1), N-methyl-D-aspartate, nicotinic acetylcholine, dopaminergic, glucocorticoid, delta-opioid, cannabinoid and cytokine receptors, gamma-amino butyric acid (GABA) and intracellular messenger systems, transcription, neuroprotective and neurogenic factors, may provide an entirely new set of potential therapeutic targets, giving hope that further major advances might be anticipated in the treatment of depressive disorder soon. The goal of this review is to give a brief overview of the major advances from monoamine-based treatment strategies, and particularly focus on the new emerging approaches in the treatment of depression.

Antidepressive Agents↗
PubMed2003

Pharmacokinetics and pharmacodynamics of cannabinoids.

Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial. They are reported to be low in humans and do not preclude legitimate therapeutic use of cannabis-based drugs. Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.

Biological Availability↗
PubMed2005

Cannabinoid CB1 receptors control conditioned drug seeking.

Recent developments have implicated cannabinoid CB1 receptors as a novel target for a new class of therapeutic agents used to treat drug addiction. CB1 receptors are expressed in the motivational circuitry of the brain and modulate drug seeking. Blockade of the CB1 receptor is particularly effective in reducing cue-induced reinstatement of drug seeking, an animal analogue of cue-induced relapse in human addicts. These relapse-preventing properties are observed with different classes of abused drug (i.e. psychostimulants, opiates, nicotine and alcohol). In addition, recent evidence indicates a more general role of CB1 receptors in reward-related memories, which is consistent with the proposed role of endocannabinoids in memory-related plasticity. Relapse-preventing actions and inhibitory effects on weight gain were confirmed recently in clinical trials with the CB1 antagonist rimonabant. Collectively, these clinical and preclinical studies suggest that antagonists of CB1 receptors offer a novel approach in the treatment of addictive behaviours.

Animals↗
PubMed2005

Are the cannabinoids involved in bony fish reproduction?

Following the discovery of two CB1 genes in the fish Fugu rubripes, investigations on the phylogeny of endocannabinoids have indicated that this system is highly conserved. Our study demonstrated that CB1 receptors are expressed in the CNS and gonads of two teleosts, Carassius auratus and Pelvicachromis pulcher, and they show a high percentage of sequence identity with Fugu rubripes CB(1A) and Danio rerio CB1. By means of immunohistochemistry for CB1, sGnRH, and TH, we found a codistribution of these signaling molecules in the basal telencephalon/preoptic area, which are key centers for gonadotropic regulation. We therefore suggest that endocannabinoids are possibly involved in modulating fish reproduction at both the central and peripheral levels.

Animals↗
PubMed1996

Immune regulation by cannabinoid compounds through the inhibition of the cyclic AMP signaling cascade and altered gene expression.

Immune modulation by cannabinoid compounds, although established for several decades, has remained up until recently mechanistically obscure. The identification of a novel class of G-protein coupled receptors that negatively regulate the cyclic adenosine 3':5'-monophosphate (cAMP) cascade, bind cannabinoids, and are expressed on cells within the immune system has provided new insights into the mechanism for their biologic activity. Although the role of the cAMP cascade in the regulation of immune responses is itself highly controversial, a number of laboratories recently demonstrated that aberrant regulation of this signaling pathway leads to alterations in the expression of critical immunoregulatory genes, cell cycle arrest, and decreased immune function. This profile of effects is strikingly similar to that which is induced in leukocytes in the presence of cannabinoid compounds. In the present commentary, a putative mechanism of immune regulation by cannabinoids is proposed. This mechanism is discussed in the context of decreased cAMP signaling, the transcription factors that are consequently adversely regulated, and immunologically relevant genes that ultimately exhibit altered expression.

Adjuvants, Immunologic↗
PubMed1992

Inhibition of adenylate cyclase by delta 9-tetrahydrocannabinol in mouse spleen cells: a potential mechanism for cannabinoid-mediated immunosuppression.

The ability of delta 9-Tetrahydrocannabinol (delta 9-THC) to modulate adenylate cyclase activity in mouse spleen cells was investigated. These studies were prompted by the recent identification and cloning of a G-protein coupled cannabinoid receptor localized in certain regions of the brain and the potential for a common mechanism between cannabinoid-mediated CNS effects and immunosuppression. Temporal addition studies were initially performed to identify the period of time when spleen cells in culture were most susceptible to the inhibitory effects of delta 9-THC, as measured by the day 5 IgM antibody forming cell response. delta 9-THC was only inhibitory when added to spleen cell cultures during the first 2 hr following antigen sensitization. In light of this time course, adenylate cyclase activity was measured in spleen cells incubated in the presence of 22 microM delta 9-THC for 5 min and subsequently stimulated with forskolin. delta 9-THC treated spleen cells demonstrated a 33% inhibition and a 66% inhibition in intracellular cAMP after a 5 or 15 min stimulation with forskolin, respectively. These studies suggest that inhibition of immune function by delta 9-THC may be mediated through the inhibition of intracellular cAMP early after antigen stimulation.

Adenylyl Cyclase Inhibitors↗
PubMed2004

Windows of vulnerability to psychopathology and therapeutic strategy in the adolescent rodent model.

Adolescence comes in association with puberty, when maturation and rearrangement of major neurotransmitter pathways and functions are still taking place. The neurobiological processes occurring in the brain during this developmental period have been so far poorly investigated. Yet, it is during adolescence that some major neuropsychiatric disorders may become evident, including ADHD, schizophrenia, and drug abuse. Moreover, the age-related neurobehavioural plasticity renders adolescents particularly vulnerable to the consequences of psychoactive drug exposure. In this view, there is an increased likelihood that addiction will develop when psychoactive drug use starts early during adolescence. From all these observations adolescence emerges as a critical phase in development. In the present review, we focus on recent neurobiological characterization of adolescent rats and mice. As for vulnerability to addictive behaviour, nicotine exposure during adolescence dose-dependently down-regulated levels of AMPA GluR2/3 subunits in the striatum, suggesting a reduced neurobehavioural plasticity in adult subjects. Comparable exposure during adulthood had opposite effects. It was found consistently that exposure to nicotine during adolescence, but not similar exposure in the post-adolescent period, increased the expression of specific subunits of the acetylcholine receptor in adult rats, thus enhancing the reinforcing efficacy of nicotine in a self-administration paradigm. The present data identified a specific age-window, characterized by long-term effects on behavioural and neurochemical indexes, of vulnerability. With respect to potential therapeutic approaches in ADHD, we studied the adolescent spontaneously-hypertensive-rat (SHR) in an intolerance-to-delay operant-behaviour paradigm. The model was further validated by the finding that impulsivity was reduced by chronic methylphenidate administration. Impulsive SHR animals were characterized by reduced cannabinoid CB1 receptor density in the prefrontal cortex. Interestingly, an acute cannabinoid agonist increased levels of self-control behaviour in these animals. The present data suggest that pharmacological modulation of the cannabinoid system might improve some behavioural anomalies seen in ADHD. In conclusion, modelling the adolescent phase in rats and mice appears to be useful for the investigation of determinants of vulnerability to addiction and to other early-onset neuropsychiatric disorders.

Adolescent↗
PubMed2002

Active bicarbonate-dependent secretion evoked by 5-hydroxytryptamine in porcine ileal mucosa is mediated by opioid-sensitive enteric neurons.

5-Hydroxytryptamine (5-HT) mediates intestinal hypersecretion associated with infection and inflammation. We tested the hypothesis that 5-HT-induced anion secretion is mediated by an opioid-sensitive enteric neural circuit. 5-HT, at a contraluminal concentration of 10 microM, increased short-circuit current by 58 +/- 7 microA/cm(2) in sheets of porcine ileal mucosa with attached inner submucosal plexus. Responses to 5-HT were inhibited by saxitoxin or indomethacin, and reduced in tissues bathed in Cl(-)- or HCO(3)(-)-deficient media. 5-HT action was attenuated by saxitoxin in tissues bathed in Cl(-)-free media, but not HCO(3)-free media. The delta-opioid receptor agonist [D-Pen(2,5)]enkephalin (0.1 microM) blunted the 5-HT change in short-circuit current by a mechanism sensitive to the delta-opioid receptor antagonist naltrindole. The inhibitory actions of [D-Pen(2,5)]enkephalin and saxitoxin were not additive. These results suggest that 5-HT stimulates HCO(3)(-)-dependent ion transport through a mechanism involving prostanoids and an enteric neural pathway modulated by opioids.

Analgesics, Opioid↗
PubMed2002

Cannabis: old medicine with new promise for neurological disorders.

Marijuana is a complex substance containing over 60 different forms of cannabinoids, the active ingredients. Cannabinoids are now known to have the capacity for neuromodulation, via direct, receptor-based mechanisms at numerous levels within the nervous system. These have therapeutic properties that may be applicable to the treatment of neurological disorders; including anti-oxidative, neuroprotective, analgesic and anti-inflammatory actions; immunomodulation, modulation of glial cells and tumor growth regulation. This article reviews the emerging research on the physiological mechanisms of endogenous and exogenous cannabinoids in the context of neurological disease.

Animals↗
PubMed2001

Localization and mechanisms of action of cannabinoid receptors at the glutamatergic synapses of the mouse nucleus accumbens.

Despite the role of excitatory transmission to the nucleus accumbens (NAc) in the actions of most drugs of abuse, the presence and functions of cannabinoid receptors (CB1) on the glutamatergic cortical afferents to the NAc have never been explored. Here, immunohistochemistry has been used to show the localization of CB1 receptors on axonal terminals making contacts with the NAc GABAergic neurons. Electrophysiological techniques in the NAc slice preparation revealed that cannabimimetics [WIN 55,212,2 (WIN-2) and CP55940] strongly inhibit stimulus-evoked glutamate-mediated transmission. The inhibitory actions of WIN-2 were dose-dependent (EC(50) of 293 +/- 13 nm) and reversed by the selective CB1 antagonist SR 141716A. In agreement with a presynaptic localization of CB1 receptors, WIN-2 increased paired-pulse facilitation, decreased miniature EPSC (mEPSC) frequency, and had no effect on the mEPSCs amplitude. Perfusion with the adenylate cyclase activator forskolin enhanced glutamatergic transmission but did not alter presynaptic CB1 actions, suggesting that cannabinoids inhibit glutamate release independently from the cAMP-PKA cascade. CB1 did not reduce evoked transmitter release by inhibiting presynaptic voltage-dependent Ca(2+) currents through N-, L-, or P/Q-type Ca(2+) channels, because CB1 inhibition persisted in the presence of omega-Conotoxin-GVIA, nimodipine, or omega-Agatoxin-IVA. The K(+) channel blockers 4-aminopyridine (100 micrometer) and BaCl(2) (300 micrometer) each reduced by 40-50% the inhibitory actions of WIN-2, and their effects were additive. These data suggest that CB1 receptors are located on the cortical afferents to the nucleus and can reduce glutamate synaptic transmission within the NAc by modulating K(+) channels activity.

Action Potentials↗
PubMed1999

The neurobiology of cannabinoid analgesia.

The discovery of cannabinoid receptors and their putative endogenous ligands raises questions as to the nature of the effects produced by cannabinoids on neural circuits that mediate pain and whether endogenous cannabinoids produced by the brain or in the periphery serve naturally to modulate pain. A sizable body of previous work showed that cannabinoid agonists suppress pain behavior in a variety of models of acute and chronic pain. However, at appropriate doses, cannabinoids also profoundly suppress motor behavior (see Sañudo-Peña et al., this volume), which complicates the interpretation of behavioral analgesia since a motor response is the endpoint of virtually all such studies. Studies conducted in this laboratory used biochemical and neurophysiological measures to determine whether cannabinoids suppress nociceptive neurotransmission. The results showed that cannabinoids suppress nociceptive neurotransmission at the level of the spinal cord and the thalamus. These effects are reversible, receptor mediated, selective for painful as opposed to nonpainful somatic stimuli, and track the behavioral analgesia both in time course and potency.

Analgesia↗
PubMed1999

Cannabinoid modulation of dynorphin A: correlation to cannabinoid-induced antinociception.

Intrathecal administration of anandamide, delta9-tetrahydrocannabinol (THC) and (-)-3-[2-hydroxy-4-(1,1-dimethyheptyl)ptyl)phenyl]-4-(3-hydr oxypropyl)-cicloexan-1-ol (CP55,940) induced spinal antinociception accompanied by differential kappa-opioid receptor involvement and dynorphin A peptide release. Antinociception using the tail-flick test was induced by the classical cannabinoid THC and was blocked totally by 17,17'-bis(cyclopropylmethyl)-6',6,7,7'-tetrahydro-4,5,4'5'-diepoxy++ +-6,6'-(imino)[7,7'-bimorphinan]-3,3',14,14'-tetrol (norbinaltorphimine) indicating a significant and critical kappa-opioid receptor component. The endogenous cannabinoid, anandamide and the non-classical bicyclic cannabinoid, CP55,940, induced non-nor-BNI-sensitive effects. The N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazo le-carboxamide (SR141716A)-mediated attenuation of spinal antinociception imparted by the various cannabinoids indicates cannabinoid CB1 receptor involvement. THC-induced an enhancement of immunoreactive dynorphin A release which coincided with the onset, but not duration antinociception. The release of dynorphin A was also attenuated by SR141716A suggesting it is cannabinoid CB1 receptor-mediated. These data indicate a critical role for dynorphin A release in the initiation of the antinociceptive effects of the cannabinoids at the spinal level.

Analgesics↗
PubMed2001

Cannabinoid-induced presynaptic inhibition of glutamatergic EPSCs in substantia gelatinosa neurons of the rat spinal cord.

The effect of cannabinoids on excitatory transmission in the substantia gelatinosa was investigated using intracellular recording from visually identified neurons in a transverse slice preparation of the juvenile rat spinal cord. In the presence of strychnine and bicuculline, perfusion of the cannabinoid receptor agonist WIN55,212-2 reduced the frequency and the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). Furthermore, the frequency of miniature EPSCs (mEPSCs) was also decreased by WIN55,212-2, whereas their amplitude was not affected. Similar effects were reproduced using the endogenous cannabinoid ligand anandamide. The effects of both agonists were blocked by the selective CB(1) receptor antagonist SR141716A. Electrical stimulation of high-threshold fibers in the dorsal root evoked a monosynaptic EPSC in lamina II neurons. In the presence of WIN55,212-2, the amplitude of the evoked EPSC (eEPSCs) was reduced, and the paired-pulse ratio was increased. The reduction of the eEPSC following CB(1) receptor activation was unlikely to have a postsynaptic origin because the response to AMPA, in the presence of 1 microM TTX, was unchanged. To investigate the specificity of this synaptic inhibition, we selectively activated the nociceptive C fibers with capsaicin, which induced a strong increase in the frequency of EPSCs. In the presence of WIN55,212-2, the response to capsaicin was diminished. In conclusion, these results strongly suggest a presynaptic location for CB(1) receptors whose activation results in inhibition of glutamate release in the spinal dorsal horn. The strong inhibitory effect of cannabinoids on C fibers may thereby contribute to the modulation of the spinal excitatory transmission, thus producing analgesia at the spinal level.

Analgesics↗
PubMed1999

Cannabinol-mediated inhibition of nuclear factor-kappaB, cAMP response element-binding protein, and interleukin-2 secretion by activated thymocytes.

Cannabinol (CBN), an immunosuppressive cannabinoid and ligand for the peripheral cannabinoid receptor CB2, inhibits the cAMP signaling cascade in forskolin-stimulated thymocytes. The objective of the present studies was to further characterize the mechanism of CBN immune modulation by investigating its effects on interleukin-2 (IL-2) secretion, cAMP response element (CRE), and kappaB DNA binding activity in phorbol ester (phorbol-12-myristate-13-acetate, PMA) plus calcium ionophore (PMA/Io)-activated thymocytes. PMA/Io treatment induced CRE and kappaB DNA binding activity that was attenuated in the presence of CBN. A concomitant and concentration-related inhibition of IL-2 also was produced by CBN in PMA/Io-activated thymocytes. PMA/Io induced two CRE DNA binding complexes, a major complex consisting of a cAMP response element-binding protein (CREB)-1 homodimer, and a minor CREB-1/activating transcription factor (ATF)-2 complex. Both CRE complexes were inhibited by CBN. Conversely, two kappaB DNA binding complexes were observed, but only one was PMA/Io-inducible. However, the DNA binding activity of both complexes was diminished in the presence of CBN. The PMA/Io-inducible kappaB complex was a p65/c-Rel heterodimer. Analysis of up-stream regulation revealed a decrease in phosphorylated CREB/ATF nuclear proteins in PMA/Io-activated thymocytes after CBN treatment. Similarly, CBN prevented the phosphorylation-dependent degradation of the nuclear factor-kappaB inhibitory protein IkappaB-alpha. These results provide a potential link between the CBN-mediated inhibition of thymocyte function, including IL-2 production, and the inhibition of two critical transcription factor families, CREB/ATF and NF-kappaB/Rel.

Activating Transcription Factor 1↗
PubMed2004

[The pharmacological and rational theory for the drug development of Parkinson's disease].

The basal ganglia in the brain contains glutamate, dopamine, serotonin, noradrenaline, CCK, adenosine, opioid, cannabinoid, etc. These agents contribute to keep motor control and modulation of the agent may be a cue to the treatment of movement disorders. D1 or D2 dopamine receptor agonists increase locomotor activity in MPTP-treated common marmosets which showed decreased locomotor activity and decreased number of dopamine neurons in the substantia nigra. Using this model of parkinsonism, NMDA receptor antag-onists, antimuscarinic receptor antagonists, 5-HT1A receptor agonists, adenosine receptor antagonists were showed to reverse the impaired movement of the model animals. The results may contribute to the development of new drugs for the treatment of Parkinson's disease.

Animals↗
PubMed1998

Cannabinoid modulation of wide dynamic range neurons in the lumbar dorsal horn of the rat by spinally administered WIN55,212-2.

The effects of spinally administered cannabinoids on nociceptive responses of wide dynamic range (WDR) neurons in the lumbar spinal cord were investigated in urethane-anesthetized rats. Noxious thermal stimulation was applied with a Peltier device to regions of the ipsilateral hindpaw corresponding to the receptive fields of isolated neurons. WIN55,212-2 (100 microg, i.t.), applied topically on the dorsal spinal surface, suppressed noxious heat-evoked activity in spinal WDR neurons. By contrast, responsiveness was unchanged following administration of either vehicle or WIN55,212-3, the receptor-inactive enantiomer. WIN55,212-2, administered intrathecally to separate rats, produced antinociceptive effects in the tail-flick test with a time course and efficacy that paralleled the suppression of noxious heat-evoked activity. These results suggest that cannabinoid modulation of spinal nociceptive processing involves direct actions in the spinal dorsal horn and is related to the antinociceptive effects of intrathecally administered cannabinoids.

Animals↗