Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cannabinoids”

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 469 records · Page 26Linked to original sources
PubMed1999

Cannabinoids as potential new analgesics.

Among other pharmacological properties analgesia is one of the important features of cannabinoids with therapeutical prospects. Cannabinoids have been shown to produce antinociception in experimental animals and humans. Recently a new system of neuromodulation based upon the existence of cannabinoid receptors and their endogenous agonists has emerged. This has been proposed as another of the endogenous pain control systems. Current evidence indicate an interaction between cannabinoid and opioid systems, the latter being of known relevance in nociception. The fact that either exogenous or endogenous opioids enhanced cannabinoid-induced antinociception suggests simultaneous activation of both opioid and cannabinoid receptors by drugs as a new analgesic strategy.

Analgesia↗
PubMed2003

Differential cannabinoid-induced electrophysiological effects in rat ventral tegmentum.

Cannabinoids are known to exert mainly excitatory effects on dopaminergic cells of the ventral tegmental area (VTA). We have utilized an in vivo multiple-single unit electrophysiological approach to assess different neuronal contributions that may ultimately lead to excitation in this area. Baseline neuron recordings, using low impedance microwires, showed a variety of waveforms with a wide range of durations (0.8-3.2 ms). In the first experiment systemic injection of the potent cannabinoid agonist HU210 (100 microg/kg, i.p.) led predominantly to an increase in firing rate (approximately 214%, compared to pre-drug) in slowly firing cells with broad action potentials, possibly driven by a majority of presumed dopaminergic neurons (n = 31). However, the firing rate of some units was either unaffected (<25%, n = 9) or even decreased (approximately 67%, n = 9) following cannabinoid injection concomitantly with excitation. Apomorphine (75 microg/kg, i.p.) injected following HU210 produced a marked inhibition of both responses (approximately 76%) in 39 out of 49 cells. The second group of animals was treated with the CB(1) receptor antagonist SR141716A (1 mg/kg, i.p.), which had no effect when injected alone but prevented all HU210-evoked changes in firing rate suggesting that cannabinoid receptors mediated the observed responses (n = 39). Taken together, the present results suggest that the observed actions of cannabinoids may involve complex neurotransmitter interactions leading to differential effects on dopamine release. These heterogeneous neuronal responses are likely to underly the behavioural discrepancies reported in animal models of cannabinoid reinforcement.

Action Potentials↗
PubMed1996

Molecular neurobiology of the cannabinoid receptor.

Marijuana is currently the most widely abused street drug. However, the functional significance of the cannabinoid receptor system in health and disease includes the use of cannabinoids as analgesics, antiemetics in cancer patients, anticonvulsants for epilepsy, and as antiglaucoma agents as well as immunomodulatory agents. Our knowledge of the mechanisms of action of cannabinoids has increased greatly in the past several years. Two cannabinoid receptors have been identified to date: one is located predominantly in the central nervous system (CBI), whereas the other is expressed in peripheral tissues (CB2). Both are members of the G-protein-coupled receptor family and couple to inhibition of adenylyl cyclase (as well as additional second messenger systems), in transfected cells expressing these receptors, and in the nervous system. An endogenous ligand has been isolated for the CBI receptor; it is arachidonic acid ethanolamide, or anandamide. Candidate endogenous ligands for the CB2 receptor have also been described. Another development is the discovery of a selective antagonist for the CBI receptor. The distribution of the cannabinoid receptor subtypes has been mapped by receptor autoradiography, RT-PCR and in situ hybridization. These new research tools will aid in the elucidation of the physiological role of the endogenous cannabinoid system.

Amino Acid Sequence↗
PubMed1997

Changes in rat spleen cannabinoid receptors after chronic CP-55,940: an autoradiographic study.

We examined whether cannabinoid receptor density changes in the rat spleen after in vivo chronic exposure to cannabinoids. Rats received daily injections of 0.4 mg/kg IP of the synthetic cannabinoid receptor ligand CP-55,940 for 11 days. One h after the last injection on day 11, the rats were killed and spleen coronal sections were processed for receptor binding autoradiography with 10 nM of [3H]CP-55,940 in the absence or presence of unlabeled CP-55,940 (10 microM). Densitometric analysis of the autoradiograms showed significant loss of [3H]CP-55,940 binding of about 42% in chronic cannabinoid-treated, tolerant rats. Our findings indicate that cannabinoid receptors basically present in immune spleen cells are down-regulated by chronic exposure to cannabinoids, suggesting a role in immune modulation and in the impairment of immune function.

Animals↗
PubMed2001

Modulation of transmitter release via presynaptic cannabinoid receptors.

Cannabis (marijuana) is not only a frequently abused drug but also has the potential for the development of useful agents for the treatment of emesis, anorexia and multiple sclerosis. In this article, the effects of modulation of transmitter release by cannabinoids in both the CNS and the PNS of various species, including humans, will be discussed. Cannabinoids inhibit neurotransmitter release via specific presynaptic cannabinoid CB1 receptors. Studies using either the CB1 receptor antagonist and inverse agonist SR141716 or CB1-receptor-deficient mice suggest that numerous presynaptic cannabinoid receptors are tonically activated by endogenous cannabinoids and/or are constitutively active. CB1-receptor-mediated inhibition of transmitter release might explain, for example, reinforcing properties and memory impairment caused by cannabinoids.

Animals↗
PubMed1999

Expression of cannabinoid receptors and their gene transcripts in human blood cells.

1. This study shows that the human cannabinoid receptors and their gene transcripts can be analyzed in blood samples when combined with polymerase chain reaction. The results also demonstrate that the expression of the cannabinoid receptors is dependent on gender and ethnic background. 2. Normal human volunteers who do not use marijuana have genes that encode for the marijuana (cannabinoid) receptor proteins. 3. Primer pairs from CB1 and CB2 cDNA coding region sequences showed identical amplified DNA band sizes in both DNA-PCR and reverse PCR, with human templates. This suggests that the CB1 and CB2 genes are intronless at least in their coding regions. 4. An advantage of the coding region being intronless may be that the expression of these genes will have one major RNA processing event to skip, thus making the conditions of their expression relatively quick and simple. This advantage may have implications related to the biological functions of these proteins. 5. We therefore concluded that the existence of human cannabinoid receptors and genes along with the discovery of endogenous cannabinoids (endocannabinoids) may be useful markers in elucidating the role(s) and mechanism(s) of action of cannabinoids.

Adult↗
PubMed1997

delta9-Tetrahydrocannabinol excites rat VTA dopamine neurons through activation of cannabinoid CB1 but not opioid receptors.

Behavioral, biochemical and recent electrophysiological data have increasingly implicated the involvement of dopamine in the central actions of cannabinoid compounds. However, the site and mechanism by which cannabinoids stimulate dopamine systems has been somewhat controversial. Central opioid systems have also been suggested to play a role in some cannabinoid-induced behaviors as evidenced by their attenuation in the presence of the opioid antagonist naloxone. However, recent studies using the cannabinoid receptor-selective antagonist SR141716A suggest that the central actions of psychoactive cannabinoids are mediated principally through activation of CB1 receptors. Using single cell electrophysiological recordings in the rat we assessed the effects of both SR141716A and naloxone on delta9-tetrahydrocannabinol (THC)-induced activation of ventral tegmental dopamine neurons. While dopamine cell firing was dose-dependently increased following cumulative dosing with delta9-THC it was partially or completely inhibited following pretreatment with 0.5 and 2 mg/kg SR141716A, respectively. However, 1 and 10 mg/kg naloxone failed to alter the response to delta9-THC. These data provide the first evidence that delta9-THC-induced changes in mesolimbic dopamine neuronal activity are mediated by the CB1 cannabinoid receptor, but a causal link for the involvement of opioid systems could not be established.

Animals↗
PubMed2003

Topical cannabinoid antinociception: synergy with spinal sites.

Analgesic effects of cannabimimetic compounds have been known to be related to their central effects. Cannabinoid receptors also exist in the periphery but their role in pain perception has been remained to be clarified. Therefore, we assessed topical antinociceptive effects of WIN 55, 212-2, a mixed CB(1) and CB(2) receptors agonist, in mice using tail-flick test. Immersion of the tail of mouse into the WIN 55, 212-2 solution produced dose-dependent antinociception. This antinociceptive activity was limited to the portion of the tail exposed to WIN 55, 212-2. The antinociceptive response was dependent on duration of exposure to WIN 55, 212-2 solution. The topical antinociceptive effects of WIN 55, 212-2 were dose dependently blocked by topical pretreatment of CB(1) receptor-selective antagonist, AM 251. Thus, topical antinociceptive action of WIN 55, 212-2 involve CB(1) receptors. Intrathecal (i.th.) administration of WIN 55, 212-2 produced a dose-dependent antinociceptive effect. Interestingly, ineffective i.th. doses of WIN 55, 212-2 produced a marked antinociception when combined with topical application of WIN 55, 212-2 and topical antinociceptive effect was potentiated. The dose-response curve of i.th. WIN 55, 212-2 was shifted to the left 15-fold by topical WIN 55, 212-2. This finding suggests that there is an antinociceptive synergy between peripheral and spinal sites of cannabinoid action and it also implicates that local activation of cannabinoid system may regulate pain initiation in cutaneous tissue. Our findings support that cannabinoid system participates in buffering the emerging pain signals at the peripheral sites in addition to their spinal and supraspinal sites of action. In addition, an antinociceptive synergy between topical and spinal cannabinoid actions exists. These results also indicate that topically administered cannabinoid agonists may reduce pain without the dysphoric side effects and abuse potential of centrally acting cannabimimetic drugs.

Administration, Topical↗
PubMed1999

Cannabinoid receptors undergo axonal flow in sensory nerves.

Cannabinoids modulate nociceptive processing through central and peripheral mechanisms. The present study was conducted to evaluate axonal flow of cannabinoid receptors from the dorsal root ganglion to the periphery and to identify the putative involvement of CB1 and/or CB2 receptor subtypes. The sciatic nerve was tightly ligated to dam the flow of cannabinoid receptors to the periphery. The densities of cannabinoid receptors proximal and distal to one or two tightly constrictive ligatures was evaluated using in vitro receptor binding and high-resolution emulsion autoradiography. In both models, [3H]CP55,940 binding accumulated proximal as opposed to distal to the ligature. These data indicate that axonal transport of cannabinoid receptors to the periphery was occluded by tight constriction of the sciatic nerve. In situ hybridization histochemistry revealed that dorsal root ganglia cells synthesize CB1 but not CB2 receptor messenger RNA. By contrast, CB2 messenger RNA was highly expressed in sections of rat spleen that were processed together with the dorsal root ganglia, as previously described. These data demonstrate that neuronal cannabinoid CB1 receptors are synthesized in cells of the dorsal root ganglia and inserted on terminals in the periphery.

Animals↗
PubMed2002

Effect of the cannabinoid receptor ligand, WIN 55,212-2, on superoxide anion and TNF-alpha production by human mononuclear cells.

Cannabinoids are known to downregulate immune response but the role for cannabinoid receptors in cannabinoid-induced immunosuppression is still unclear. To address this question, the interference of CB1 and CB2 receptor antagonists with the inhibition of TNF-alpha production by synthetic cannabinoid WIN 55,212-2 was studied using human peripheral blood mononuclear cells (PBMC) in vitro. CB2 (SR 144528) but not CB1 (SR 141716A) receptor antagonist dose dependently interfered with WIN 55,212-2-induced inhibition of TNF-alpha synthesis. Also, WIN 55,212-2 decreased fMLP-induced reactive oxygen species generation in lipopolysaccharide (LPS)-primed PBMC. However, the high concentrations of cannabinoid receptor ligands needed to achieve significant effects suggest that the observed effects may be in part cannabinoid receptor independent.

Benzoxazines↗
PubMedDate not supplied

Cannabinoid receptors on goldfish retinal bipolar cells: electron-microscope immunocytochemistry and whole-cell recordings.

Cannabinoid CB1 receptors are distributed throughout the CNS and interact with GABA, glutamate, and dopamine systems. Cannabinoids have effects on the visual system, some of which may have a retinal component, particularly the enhancement of photosensitivity. We used immunocytochemistry and whole-cell recording to study cannabinoids in the goldfish retina. Immunoblots of an antiserum against amino acids (1-14) of the rat CB1 receptor produced a single band in goldfish retina at about 70 kDa. Light microscope immunocytochemistry of CB1 receptor immunoreactivity (CB1R-IR) revealed intense staining of Müller cells and weaker staining of ON bipolar cells (verified with double labeling with PKC-IR) and the outer and inner plexiform layers. Ultrastructural analysis revealed that CB1R-IR was localized intracellularly as well as on the plasma membrane of photoreceptor terminals, bipolar cell terminals and, rarely, amacrine cell boutons. Membrane-associated CB1R-IR was restricted to cone pedicles at sites removed from the synaptic ribbon. Regarding bipolar cells, membrane-associated CB1R-IR was found at 93% of the synaptic terminals in sublamina b (ON-type) and only at 33% of the synaptic terminals in sublamina a (OFF-type). Whole-cell recordings from large ON-type Mb bipolar cells showed that the delayed rectifier (I(K(V))) was rapidly and reversibly inhibited by 1 microM of the cannabinoid agonists CP 54490 and (+)-WIN 55212-2, effects blocked completely by the antagonist SR 141716A (1 microM). Inhibition of I(K(V)) in the Mb bipolar cells by cannabinoids should result in a more tonic ON response to increments of light. As such, cannabinoids may play a role in modulating the temporal aspects of signaling in the retina.

Animals↗
PubMed1999

Effect of the cannabinoid receptor agonist WIN55212-2 on sympathetic cardiovascular regulation.

1. The aim of the present study was to analyse the cardiovascular actions of the synthetic CB1/CB2 cannabinoid receptor agonist WIN55212-2, and specifically to determine its sites of action on sympathetic cardiovascular regulation. 2. Pithed rabbits in which the sympathetic outflow was continuously stimulated electrically or which received a pressor infusion of noradrenaline were used to study peripheral prejunctional and direct vascular effects, respectively. For studying effects on brain stem cardiovascular regulatory centres, drugs were administered into the cisterna cerebellomedullaris in conscious rabbits. Overall cardiovascular effects of the cannabinoid were studied in conscious rabbits with intravenous drug administration. 3. In pithed rabbits in which the sympathetic outflow was continuously electrically stimulated, intravenous injection of WIN55212-2 (5, 50 and 500 microg kg(-1)) markedly reduced blood pressure, the spillover of noradrenaline into plasma and the plasma noradrenaline concentration, and these effects were antagonized by the CB1 cannabinoid receptor-selective antagonist SR141716A. The hypotensive and the sympathoinhibitory effect of WIN55212-2 was shared by CP55940, another mixed CB1/CB2 cannabinoid receptor agonist, but not by WIN55212-3, the enantiomer of WIN55212-2, which lacks affinity for cannabinoid binding sites. WIN55212-2 had no effect on vascular tone established by infusion of noradrenaline in pithed rabbits. 4. Intracisternal application of WIN55212-2 (0.1, 1 and 10 microg kg(-1)) in conscious rabbits increased blood pressure and the plasma noradrenaline concentration and elicited bradycardia; this latter effect was antagonized by atropine. 5. In conscious animals, intravenous injection of WIN55212-2 (5 and 50 microg kg(-1)) caused bradycardia, slight hypotension, no change in the plasma noradrenaline concentration, and an increase in renal sympathetic nerve firing. The highest dose of WIN55212-2 (500 microg kg(-1)) elicited hypotension and tachycardia, and sympathetic nerve activity and the plasma noradrenaline concentration declined. 6. The results obtained in pithed rabbits indicate that activation of CB1 cannabinoid receptors leads to marked peripheral prejunctional inhibition of noradrenaline release from postganglionic sympathetic axons. Intracisternal application of WIN55212-2 uncovered two effects on brain stem cardiovascular centres: sympathoexcitation and activation of cardiac vagal fibres. The highest dose of systemically administered WIN55212-2 produced central sympathoinhibition; the primary site of this action is not known.

Analgesics↗
PubMed2001

Effects of cannabinoids on adrenaline release from adrenal medullary cells.

1. The objective of the present study was to analyse the peripheral effects of cannabinoids on adrenaline release from adrenal chromaffin cells. 2. In pithed rabbits with electrically stimulated sympathetic outflow, intravenous injection of the cannabinoid receptor agonists WIN55212-2 and CP55940 (5, 50 and 500 microg x kg(-1)) markedly lowered the plasma adrenaline concentration. The effect of WIN55212-2 was attenuated by the selective CB1 cannabinoid receptor antagonist SR141716A (500 microg x kg(-1)). WIN55212-3 (same doses as WIN55212-2), the enantiomer of WIN55212-2 lacking affinity for cannabinoid receptors, had no effect on the plasma adrenaline concentration. 3. In rabbit isolated adrenal glands, the release of adrenaline elicited by electrical stimulation was measured by fast cyclic voltammetry. Electrically-evoked adrenaline release was inhibited by WIN55212-2 (0.3, 1, 3 and 10 microM) and this effect was antagonized by SR141716A (1 microM). The non-cholinergic component of adrenaline release observed after blockade of nicotinic (by hexamethonium 100 microM) and muscarinic (by atropine 0.5 microM) acetylcholine receptors was not depressed by WIN55212-2. WIN55212-3 (10 microM) had no effect on adrenaline release. 4. No detectable specific CB1 receptor binding and mRNA expression were found in rabbit adrenal glands with autoradiography and in situ hybridization. 5. The results show that cannabinoids inhibit adrenaline secretion in rabbit isolated adrenal glands; the likely mechanism is a presynaptic CB1 receptor-mediated inhibition of acetylcholine release from preganglionic sympathetic neurons. The inhibition of adrenaline secretion in adrenal glands most probably accounts for the decrease in the plasma adrenaline concentration observed after cannabinoid administration in pithed rabbits.

Adrenal Glands↗
PubMed2002

Direct inhibition by cannabinoids of human 5-HT3A receptors: probable involvement of an allosteric modulatory site.

Excised outside-out patches from HEK293 cells stably transfected with the human (h) 5-HT3A receptor cDNA were used to determine the effects of cannabinoid receptor ligands on the 5-HT-induced current using the patch clamp technique. In addition, binding studies with radioligands for 5-HT3 as well as for cannabinoid CB1 and CB2 receptors were carried out. The 5-HT-induced current was inhibited by the following cannabinoid receptor agonists (at decreasing order of potency): 9-THC, WIN55,212-2, anandamide, JWH-015 and CP55940. The WIN55,212-2-induced inhibition was not altered by SR141716A, a CB1 receptor antagonist. WIN55,212-3, an enantiomer of WIN55,212-2, did not affect the 5-HT-induced current. WIN55,212-2 did not change the EC50 value of 5-HT in stimulating current, but reduced the maximum effect. The CB1 receptor ligand [3H]-SR141716A and the CB1/CB2 receptor ligand [3H]-CP55940 did not specifically bind to parental HEK293 cells. In competition experiments on membranes of HEK293 cells transfected with the h5-HT3A receptor cDNA, WIN55,212-2, CP55940, anandamide and SR141716A did not affect [3H]-GR65630 binding, but 5-HT caused a concentration dependent-inhibition. In conclusion, cannabinoids stereoselectively inhibit currents through recombinant h5-HT3A receptors independently of cannabinoid receptors. Probably the cannabinoids act allosterically at a modulatory site of the h5-HT3A receptor. Thus the functional state of the receptor can be controlled by the endogenous ligand anandamide. This site is a potential target for new analgesic and antiemetic drugs.

Allosteric Site↗
PubMed2004

Modulation of trigeminal sensory neuron activity by the dual cannabinoid-vanilloid agonists anandamide, N-arachidonoyl-dopamine and arachidonyl-2-chloroethylamide.

1. Peripheral cannabinoids have been shown to suppress nociceptive neurotransmission in a number of behavioral and neurophysiological studies. It is not known, however, whether cannabinoids exert this action through direct interactions with nociceptors in the periphery and/or if other processes are involved. To gain a better understanding of the direct actions of cannabinoid-vanilloid agonists on sensory neurons, we examined the effects of these compounds on trigeminal ganglion (TG) neurons in vitro. 2. AEA (EC(50)=11.0 microM), NADA (EC(50)=857 nM) and arachidonyl-2-chloroethylamide ACEA (EC(50)=14.0 microM) each evoked calcitonin gene-related peptide (CGRP) release from TG neurons. The TRPV1 antagonists iodo-resiniferatoxin (I-RTX) and capsazepine (CPZ) each obtunded AEA-, NADA-, ACEA- and capsaicin (CAP)-evoked CGRP release with individually equivalent IC(50)'s for each of the compounds (I-RTX IC(50) range=2.6-4.0 nM; CPZ IC(50) range=523-1140 microM). 3. The pro-inflammatory mediator prostaglandin E(2) significantly increased the maximal effect of AEA-evoked CGRP release without altering the EC(50). AEA, ACEA and CAP stimulated cAMP accumulation in TG neurons in a calcium- and TRPV1-dependent fashion. Moreover, the protein kinase inhibitor staurosporine significantly inhibited AEA- and CAP-evoked CGRP release. 4. The pungency of AEA, NADA, ACEA and CAP in the rat eye-wipe assay was also assessed. Interestingly, when applied intraocularly, NADA or CAP each produced nocifensive responses, while AEA or ACEA did not. 5. Finally, the potential inhibitory effects of these cannabinoids on TG nociceptors were evaluated. Neither AEA nor ACEA decreased CAP-evoked CGRP release. Furthermore, neither of the cannabinoid receptor type 1 antagonists SR141716A nor AM251 had any impact on either basal or CAP-evoked CGRP release. AEA also did not inhibit 50 mM K(+)-evoked CGRP release and did not influence bradykinin-stimulated inositol phosphate accumulation. 6. We conclude that the major action of AEA, NADA and ACEA on TG neurons is excitatory, while, of these, only NADA is pungent. These findings are discussed in relation to our current understanding of interactions between the cannabinoid and vanilloid systems and nociceptive processing in the periphery.

Aminobutyrates↗
PubMed2007

Control of spasticity in a multiple sclerosis model is mediated by CB1, not CB2, cannabinoid receptors.

BACKGROUND AND PURPOSE: There is increasing evidence to suggest that cannabis can ameliorate muscle-spasticity in multiple sclerosis, as was objectively shown in experimental autoimmune encephalomyelitis models. The purpose of this study was to investigate further the involvement of CB1 and CB2)cannabinoid receptors in the control of experimental spasticity. EXPERIMENTAL APPROACH: Spasticity was induced in wildtype and CB1-deficient mice following the development of relapsing, experimental autoimmune encephalomyelitis. Spastic-hindlimb stiffness was measured by the resistance to flexion against a strain gauge following the administration of CB1 and CB2 agonists. KEY RESULTS: As previously suggested, some CB2-selective agonists (RWJ400065) could inhibit spasticity. Importantly, however, the anti-spastic activity of RWJ400065 and the therapeutic effect of non-selective CB1/CB2 agonists (R(+)WIN55,212-2 and CP55, 940) was lost in spastic, CB1-deficit mice. CONCLUSIONS AND IMPLICATIONS: The CB1 receptor controls spasticity and cross-reactivity to this receptor appears to account for the therapeutic action of some CB2 agonists. As cannabinoid-induced psychoactivity is also mediated by the CB1 receptor, it will be difficult to truly dissociate the therapeutic effects from the well-known, adverse effects of cannabinoids when using cannabis as a medicine. The lack of knowledge on the true diversity of the cannabinoid system coupled with the lack of total specificity of current cannabinoid reagents makes interpretation of in vivo results difficult, if using a purely pharmacological approach. Gene knockout technology provides an important tool in target validation and indicates that the CB1 receptor is the main cannabinoid target for an anti-spastic effect.

Animals↗
PubMed1991

Molecular cloning of a human cannabinoid receptor which is also expressed in testis.

A cDNA clone encoding a receptor protein which presents all the characteristics of a guanine-nucleotide-binding protein (G-protein)-coupled receptor was isolated from a human brain stem cDNA library. The probe used (HGMP08) was a 600 bp DNA fragment amplified by a low-stringency PCR, using human genomic DNA as template and degenerate oligonucleotide primers corresponding to conserved sequences amongst the known G-protein-coupled receptors. The deduced amino acid sequence encodes a protein of 472 residues which shares 97.3% identity with the rat cannabinoid receptor cloned recently [Matsuda, Lolait, Brownstein, Young & Bronner (1990) Nature (London) 346, 561-564]. Abundant transcripts were detected in the brain, as expected, but lower amounts were also found in the testis. The same probe was used to screen a human testis cDNA library. The cDNA clones obtained were partially sequenced, demonstrating the identity of the cannabinoid receptors expressed in both tissues. Specific binding of the synthetic cannabinoid ligand [3H]CP55940 was observed on membranes from Cos-7 cells transfected with the recombinant receptor clone. In stably transfected CHO-K1 cell lines, cannabinoid agonists mediated a dose-dependent and stereoselective inhibition of forskolin-induced cyclic AMP accumulation. The ability to express the human cannabinoid receptor in mammalian cells should help in developing more selective drugs, and should facilitate the search for the endogenous cannabinoid ligand(s).

Amino Acid Sequence↗
PubMed2001

Effects of cannabinoids on prefrontal neuronal responses to ventral tegmental area stimulation.

Cannabinoids activate the firing of mesoprefrontocortical dopamine neurons and release dopamine in the prefrontal cortex. This study was undertaken with the aim of clarifying the interaction between cannabinoids and mesocortical system in the prefrontal cortex. The effect of Delta9-tetrahydrocannabinol (Delta9-THC) and the synthetic CB1 agonist WIN55,212-2 (WIN) was studied by extracellular single unit recordings, in chloral hydrate anaesthetised rats, on the spontaneous activity of pyramidal neurons and on the inhibition produced on these neurons by the electrical stimulation of the ventral tegmental area (VTA). Intravenously administered Delta9-THC and WIN (1.0 and 0.5 mg/kg, respectively), increased the firing rate of pyramidal neurons projecting to the VTA. VTA stimulation produced a phasic inhibition (167 +/- 6 ms) in 79% of prefrontal cortex pyramidal neurons. Delta9-THC and WIN reverted this inhibition in 73% and 100% of the neurons tested, respectively. The subsequent administration of the selective CB1 antagonist SR141716A (1 mg/kg) readily suppressed the effects of both cannabinoids and restored the inhibitory response to VTA stimulation. Moreover, when administered alone, SR141716A prolonged the inhibition in 55.6% of the neurons tested. The results indicate that stimulation of CB1 receptors by cannabinoids results in an enhanced excitability of prefrontal cortex pyramidal neurons as indexed by the suppression of the inhibitory effect of VTA stimulation and by the increase in firing rate of antidromically identified neurons projecting to the VTA. Furthermore, our results support the view that endogenous cannabinoids exert a negative control on dopamine activity in the prefrontal cortex. This study may be relevant in helping to understand the influence of cannabinoids on cognitive processes mediated by the prefrontal cortex.

Action Potentials↗