Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of the present study was to examine the time-related effects of repeated administration of Delta9-tetrahydrocannabinol during 1, 3, 7 and 14 days on cannabinoid and mu-opioid receptor agonist-stimulated [35S]GTPgammaS binding, and CB1 cannabinoid receptor and proenkephalin gene expression in the caudate-putamen. Repeated administration with Delta9-tetrahydrocannabinol produced a time-related reduction in cannabinoid receptor synthesis and activation of signal transduction mechanisms in the caudate-putamen. Indeed, WIN-55,212-2-stimulated [35S]GTPgammaS binding decreased 24% on day 1 and then progressively decreased finding a 42% decrease on day 14. Similarly, CB1 cannabinoid receptor mRNA levels decreased (22%) on day 3, reaching 50% reduction on day 7. In contrast, a pronounced increase is detected in DAMGO-stimulated [35S]GTPgammaS binding and proenkephalin mRNA levels in the caudate-putamen. The highest degree of increase was reached on day 7 of the treatment (35% of proenkephalin mRNA levels and 62% of DAMGO-stimulated [35S]GTPgammaS binding) and then values slightly decreased on day 14. Taken together, the results of the present study indicate that, in the caudate-putamen, repeated administration with Delta9-tetrahydrocannabinol produces a time-related increase in proenkephalin gene expression and mu-opioid receptor activation of G-proteins, and a time-related decrease in CB1 cannabinoid receptor gene expression and reduction in CB1 cannabinoid receptor activation of G-proteins. These results also suggest a possible interaction between the cannabinoid and opioid systems in the caudate-putamen which may be potentially relevant in the understanding of the alterations of motor behavior that occur after prolonged exposure to cannabinoids.
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PMID:Time-dependent differences of repeated administration with Delta9-tetrahydrocannabinol in proenkephalin and cannabinoid receptor gene expression and G-protein activation by mu-opioid and CB1-cannabinoid receptors in the caudate-putamen. 1010 Dec 41

1. The rostral ventromedial medulla (RVM) is thought to play a crucial role in the antinociceptive actions of cannabinoids. This study examined the actions of the cannabinoid receptor agonist, WIN55,212-2, on membrane properties and GABAergic synaptic transmission in RVM neurons using whole cell patch clamp recordings in brain slices. 2. WIN55,212-2 (3 microM) had no effect on membrane K+ conductance of primary or secondary RVM neurons. Primary neurons responded to the kappa-opioid receptor agonist U69,593 (300 nM - 1 microM). Secondary neurons responded to the mu,delta-opioid receptor agonist met-enkephalin (10 microM). 3. WIN55,212-2 reduced the amplitude of electrically evoked (GABAergic) inhibitory postsynaptic currents (IPSCs) in all neurons (58%, pEC50=6.2+/-0.1). The inhibition was reversed by the CB1 receptor selective antagonist, SR141716 (3 microM). WIN55,212-2 also produced relative facilitation of the second IPSC to paired evoked IPSCs. 4. WIN55,212-2 and met-enkephalin reduced the rate of spontaneous miniature IPSCs in all cells (44 and 53%), but had no effect on their amplitude distributions or kinetics. 5. These results suggest that the antinociceptive actions of cannabinoids within RVM are primarily due to presynaptic inhibition of GABAergic neurotransmission. The neuronal substrates of cannabinoid actions in RVM therefore differ from those of opioids, which have both pre- and postsynaptic inhibitory actions.
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PMID:Cannabinoid receptor activation inhibits GABAergic neurotransmission in rostral ventromedial medulla neurons in vitro. 1043 1

Cannabinoid receptors are widely distributed in the nuclei of the extrapyramidal motor and mesolimbic reward systems; their exact functions are, however, not known. The aim of the present study was to characterize the effects of cannabinoids on the electrically evoked release of endogenous dopamine in the corpus striatum and the nucleus accumbens. In rat brain slices dopamine release elicited by single electrical pulses was determined by fast cyclic voltammetry. Dopamine release was markedly inhibited by the OP2 opioid receptor agonist U-50488 and the D2/D3 dopamine receptor agonist quinpirole, indicating that our method is suitable for studying presynaptic modulation of dopamine release. In contrast, the CB1/CB2 cannabinoid receptor agonists WIN55212-2 (10(-6) M) and CP55940 (10(-6)-10(-5) M) and the CB1 cannabinoid receptor antagonist SR141716A (10(-6) M) had no effect on the electrically evoked dopamine release in the corpus striatum and the nucleus accumbens. The lack of a presynaptic effect on terminals of nigrostriatal and mesolimbic dopaminergic neurons is in accord with the anatomical distribution of cannabinoid receptors: The perikarya of these neurons in the substantia nigra and the ventral tegmental area do not synthesize mRNA, and hence protein, for CB1 and CB2 cannabinoid receptors. It is therefore unlikely that presynaptic modulation of dopamine release in the corpus striatum and the nucleus accumbens plays a role in the extrapyramidal motor and rewarding effects of cannabinoids.
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PMID:Effects of cannabinoids on dopamine release in the corpus striatum and the nucleus accumbens in vitro. 1046 98

Previous research in this laboratory concerning delta9-tetrahydrocannabinol-induced spinal antinociception indicated the critical role of dynorphin A-(1-17) in spinal antinociception following acute intrathecal (i.t.) administration. In the present study, tolerance development to delta9-tetrahydrocannabinol-induced spinal antinociception attenuated delta9-tetrahydrocannabinol-induced modulation of immunoreactive dynorphin A-(1-17). These data indicate that at lower doses of drug, desensitization of the cannabinoid receptor inhibits stimulation of downstream dynorphinergic neurons. However, at higher doses of drug, desensitization is overcome and spinal dynorphin A concentrations are increased by delta9-tetrahydrocannabinol. Antinociception in the absence of elevated dynorphin A-(1-17) levels in the tolerant rat suggests that factors other than the attenuated dynorphin release are components of antinociception in the tolerant state. The shift from the critical role of dynorphin A in cannabinoid antinociception vs. that in the non-tolerant state may indicate tolerance also at the kappa-opioid receptor, a role as yet undetermined.
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PMID:A diminution of delta9-tetrahydrocannabinol modulation of dynorphin A-(1-17) in conjunction with tolerance development. 1055 77

We have studied the effects of the cannabinoid receptor agonists (R)-(+)[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2, 3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN 55,212-2, 0. 3-5 mg/kg, i.p.) and (-)-cis-3-[2-hydroxy-4-(1, 1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) (CP 55,940, 0.03-1 mg/kg, i.p.), the cannabinoid CB(1) receptor antagonist (N-piperidin-1-yl)-5-(4-chlorophenyl)-1-2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A, 0. 3-5 mg/kg, i.p.) and the cannabinoid CB(2) receptor antagonist N-[-(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazo le- 3-carboxamide (SR144528, 1 mg/kg, i.p.) on intestinal motility, defaecation and castor-oil (1 ml/100 g rat, orally)-induced diarrhoea in the rat. SR141716A, but not SR144528, increased defaecation and upper gastrointestinal transit, while WIN 55,212-2 and CP 55,940 decreased upper gastrointestinal transit but not defaecation. WIN 55,212-3 (5 mg/kg), the less active enantiomer of WIN 55,212-2, was without effect. A per se non-effective dose of SR141716A (0.3 mg/kg), but not of SR144528 (1 mg/kg) or the opioid receptor antagonist, naloxone (2 mg/kg i.p.), counteracted the inhibitory effect of both WIN 55,212-2 (1 mg/kg) and CP 55,940 (0.1 mg/kg) on gastrointestinal motility. WIN 55,212-2 did not modify castor-oil-induced diarrhoea, while CP 55,940 produced a transient delay in castor-oil-induced diarrhoea at the highest dose tested (1 mg/kg), an effect counteracted by SR141715A (5 mg/kg). These results suggest that (i) intestinal motility and defaecation could be tonically inhibited by the endogenous cannabinoid system, (ii) exogenous activation of cannabinoid CB(1) receptors produces a reduction in intestinal motility in the upper gastrointestinal tract but not in defaecation, (iii) endogenous or exogenous activation of cannabinoid CB(2) receptors does not affect defaecation or intestinal motility and (iv) the cannabinoid receptor agonist, CP 55, 940, possesses a weak and transient antidiarrhoeal effect while the cannabinoid receptor agonist, WIN 55,212-2, does not possess antidiarrhoeal activity.
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PMID:The role of cannabinoid receptors in intestinal motility, defaecation and diarrhoea in rats. 1061 17

The current study showed that potassium K current (I(K)), which is evoked at depolarizing potentials between -30 and +40 mV in cultured hippocampal neurons, was significantly reduced by exposure to the CB1 cannabinoid receptor agonist WIN 55,212-2 (WIN-2). WIN-2 (20-40 nM) produced an average 45% decrease in I(K) amplitude across all voltage steps, which was prevented by SR141716A, the CB1 receptor antagonist. The cannabinoid receptor has previously been shown to be G(i/o) protein-linked to several cellular processes; however, the decrease in I(K) was unaffected by modulators of G(i/o) proteins and agents that alter levels of protein kinase A. In contrast, CB1 receptor-mediated or direct activation of G(s) proteins with cholera toxin (CTX) produced the same decrease in I(K) amplitude as WIN-2, and the latter was blocked in CTX-treated cells. G(s) protein inhibition via GDPbetaS also eliminated the effects of WIN-2 on I(K). Consistent with this outcome, activation of protein kinase C (PKC) by arachidonic acid produced similar effects to WIN-2 and CTX. Kappa opioid receptor agonists, which also reduce I(K) amplitude via G(s) proteins, were compared with WIN-2 actions on I(K.) The kappa receptor agonist U50,488 reduced I(K) amplitude in the same manner as WIN-2, while the kappa receptor antagonist, nor-binaltorphimine, actually increased I(K) amplitude and significantly reduced the effect of co-administered WIN-2. The results indicate that CB1 and kappa receptor activation is additive with respect to I(K) amplitude, suggesting that CB1 and kappa receptors share a common G(s) protein signaling pathway involving PKC.
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PMID:Cannabinoid and kappa opioid receptors reduce potassium K current via activation of G(s) proteins in cultured hippocampal neurons. 1106 78

In the present work, we investigated in the rat the possibility of functional interaction between opiate and cannabinoid systems at immune level comparatively with the central nervous system (CNS). Moderate analgesic doses of the synthetic cannabinoid compound CP-55,940 (0.2 mg/kg, i.p.) and morphine (5 mg/kg, s.c.) significantly inhibited the ConA-induced splenocyte proliferation and natural killer (NK) cytolytic activity. The acute co-administration of the two drugs resulted in an enhancement of antinociception while they did not yield any additive inhibition of the immune parameters. The CB1 cannabinoid receptor antagonist N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A; 3 mg/kg, i.p.) and the CB2 receptor antagonist N-[(1S)-endo-1,3,3-trimethhyl bicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; 3 mg/kg, i.p.) did not block the central nor the immune effects of morphine; similarly, the opioid receptor antagonist naloxone did not attenuate CP-55,940-induced effects. Animals tolerant to CP-55,940-induced (0.2 mg/kg, i.p.; twice a day for 4 days) or morphine-induced analgesia (5 mg/kg, s.c.; twice a day for 6 days) also developed tolerance to their acute immunosuppressive effects. Concomitantly, animals became cross-resistant to the immunosuppressive effects while an asymmetric cross-tolerance developed for analgesia. Our data demonstrated the existence of an interaction between cannabinoids and opiates at the immune level that differs from the interaction present in the CNS.
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PMID:Comparative characterization in the rat of the interaction between cannabinoids and opiates for their immunosuppressive and analgesic effects. 1143 Oct 11

The goal of the present study was to elucidate the relationship between cannabinoid and opioid systems in drug dependence. The CB(1) cannabinoid receptor antagonist SR 141716A precipitated both paw tremors and head shakes in four different mouse strains that were treated repeatedly with Delta(9)-tetrahydrocannabinol (Delta(9)-THC). SR 141716A-precipitated Delta(9)-THC withdrawal was ameliorated in mu-opioid receptor knockout mice compared with the wild-type control animals and failed to occur in mice devoid of CB(1) cannabinoid receptors. An acute injection of morphine in Delta(9)-THC-dependent mice undergoing SR 1417161A-precipitated withdrawal dose dependently decreased both paw tremors, antagonist dose 50 (AD(50)) (95% CL) = 0.035 (0.03--0.04), and head shakes, AD(50) (95% CL) = 0.07 (0.04--0.12). In morphine-dependent mice, the opioid antagonist naloxone precipitated head shakes, paw tremors, diarrhea, and jumping. As previously reported, naloxone-precipitated morphine withdrawal failed to occur in mu-opioid knockout mice and was significantly decreased in CB(1) cannabinoid receptor knockout mice. Acute treatment of Delta(9)-THC in morphine-dependent mice undergoing naloxone-precipitated withdrawal blocked paw tremors, AD(50) (95% CL) = 0.5 (0.3--1.0), and head shakes AD(50) (95% CL) = 0.6 (0.57--0.74) in dose-dependent manners, but failed to diminish the occurrence of diarrhea or jumping. Finally, naloxone and SR 141716A failed to elicit any overt effects in Delta(9)-THC-dependent and morphine-dependent mice, respectively. These findings taken together indicate that the mu-opioid receptor plays a modulatory role in cannabinoid dependence, thus implicating a reciprocal relationship between the cannabinoid and opioid systems in dependence.
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PMID:Opioid and cannabinoid modulation of precipitated withdrawal in delta(9)-tetrahydrocannabinol and morphine-dependent mice. 1150 97

The behavioral consequences of acute heroin challenge (0.5 mg/kg, s.c.) were measured in rats previously submitted to repeated administration of increasing doses of the synthetic cannabinoid receptor agonist, R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate (WIN55212.2) (first day 2 mg/kg, second day 4 mg/kg, third day 8 mg/kg) or vehicle. Heroin administration to rats pretreated with vehicle produced catalepsy. The same dose of heroin in WIN55212.2-pretreated rats was followed by a marked increase of locomotor activity with stereotyped and non-stereotyped behaviors. These effects were blocked by the opioid receptor antagonist, naloxone. These findings indicate that pretreatment with WIN55212.2 produces cross-sensitization to heroin in the rat. These changes might reflect long-lasting changes of receptor population or transcriptional mechanisms in the mesolimbic system.
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PMID:Behavioral sensitization to heroin by cannabinoid pretreatment in the rat. 1151 39

Planaria, the most primitive example of centralization and cephalization of the nervous system along phylogeny, shows specific stereotyped behavioral patterns following exposure to drugs acting on neural transmission. In this study, the authors investigated the effects of exposure to the synthetic cannabinoid receptor agonist WTN55212.2 on motor activity in planaria. WTN55212.2 produced dose-dependent stimulation of motor behavior. High doses of the drug caused stereotyped activities identical to those seen previously with opioid agonists. These effects were antagonized by coexposure to cannabinoid or opioid receptor antagonists. The results indicate that functional interactions between cannabinoid and opioid systems are highly conserved along phylogeny, at least at the behavioral level.
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PMID:Cannabinoid-induced stimulation of motor activity in planaria through an opioid receptor-mediated mechanism. 1185 21


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