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Results for “Cannabinoid Receptor Modulators”

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At least 19 recordsLinked to original sources
PubMed2003

Effects of CB1 cannabinoid receptor modulating compounds on the hyperkinesia induced by high-dose levodopa in the reserpine-treated rat model of Parkinson's disease.

The present study was designed to determine the potential of CB1 cannabinoid receptor modulating compounds in the treatment of L-3,4-dihydroxyphenylalanine (L-dopa)-induced dyskinesia in Parkinson's disease. In the reserpine-treated rat model of parkinsonism, administration of a high dose of L-dopa (150 mg/kg) but not of Cl-APB (0.5 mg/kg) or quinpirole (0.5 mg/kg) produced a hyperkinetic state characterised by an increase in horizontal and vertical activity, which likely represent correlates of antiparkinsonian and dyskinetic activity, respectively. Injection of the CB1 cannabinoid receptor antagonist SR141716 (0.1-3 mg/kg) reduced the increase in vertical activity elicited by L-dopa without affecting the increase in horizontal activity. Injection of the CB1 cannabinoid receptor agonist WIN55,212-2 (0.1-3 mg/kg) reduced the L-dopa-induced increase in vertical activity and, at the highest dose only (3 mg/kg), also reduced horizontal activity elicited by L-dopa. WIN55,212-2 (1 mg/kg) reduced motor activity induced by both the D1 receptor agonist Cl-APB (0.5 mg/kg) and the D2 receptor agonist quinpirole (0.5 mg/kg) in the reserpine-treated rat. SR141716 (1 mg/kg) had no effects on motor activity induced by Cl-APB (0.5 mg/kg) nor quinpirole (0.5 mg/kg) in the reserpine-treated rat. Injection of the inhibitor of endocannabinoid transport AM404 (0.1-1 mg/kg) did not affect the increase in horizontal or vertical activity elicited by L-dopa (150 mg/kg) in the reserpine-treated rat. The data suggest that both CB1 cannabinoid receptor antagonists and agonists can modulate the behavioural effects of L-dopa and may be useful for the treatment of the dyskinesia associated with long-term L-dopa treatment of Parkinson's disease.

Adrenergic Uptake Inhibitors↗
PubMed2000

Cannabinoid receptor modulation of synapses received by cerebellar Purkinje cells.

The high density of cannabinoid receptors in the cerebellum and the degradation of motor coordination produced by cannabinoid intoxication suggest that synaptic transmission in the cerebellum may be strongly regulated by cannabinoid receptors. Therefore the effects of exogenous cannabinoids on synapses received by Purkinje cells were investigated in rat cerebellar slices. Parallel fiber-evoked (PF) excitatory postsynaptic currents (EPSCs) were strongly inhibited by bath application of the cannabinoid receptor agonist WIN 55212-2 (5 microM, 12% of baseline EPSC amplitude). This effect was completely blocked by the cannabinoid CB1 receptor antagonist SR 141716. It is unlikely that this was the result of alterations in axonal excitability because fiber volley velocity and kinetics were unchanged and a cannabinoid-induced decrease in fiber volley amplitude was very minor (93% of baseline). WIN 55212-2 had no effect on the amplitude or frequency of spontaneously occurring miniature EPSCs (mEPSCs), suggesting that the effect of CB1 receptor activation on PF EPSCs was presynaptically expressed, but giving no evidence for modulation of release processes after Ca(2+) influx. EPSCs evoked by climbing fiber (CF) stimulation were less powerfully attenuated by WIN 55212-2 (5 microM, 74% of baseline). Large, action potential-dependent, spontaneously occurring inhibitory postsynaptic currents (sIPSCs) were either severely reduced in amplitude (<25% of baseline) or eliminated. Miniature IPSCs (mIPSCs) were reduced in frequency (52% of baseline) but not in amplitude, demonstrating suppression of presynaptic vesicle release processes after Ca(2+) influx and suggesting an absence of postsynaptic modulation. The decrease in mIPSC frequency was not large enough to account for the decrease in sIPSC amplitude, suggesting that presynaptic voltage-gated channel modulation was also involved. Thus, while CB1 receptor activation reduced neurotransmitter release at all major classes of Purkinje cell synapses, this was not accomplished by a single molecular mechanism. At excitatory synapses, cannabinoid suppression of neurotransmitter release was mediated by modulation of voltage-gated channels in the presynaptic axon terminal. At inhibitory synapses, in addition to modulation of presynaptic voltage-gated channels, suppression of the downstream vesicle release machinery also played a large role.

Animals↗
PubMed2003

Sleep modulates cannabinoid receptor 1 expression in the pons of rats.

Endocannabinoids seem to play a role in the modulation of alertness. Therefore, we measured cannabinoid receptor 1 (CB1R) protein by Western blot and messenger RNA (mRNA) by reverse transcription-polymerase chain reaction in the pons of rats across the 24-h period. We performed evaluations every 4 h beginning at 09:00 h. Rats were under a controlled light/dark cycle 12:12 (lights on at 08:00 h). Our data suggest that the expression of CB1R gene depends on diurnal variations, with maximum expression at 13:00 h for protein and 21:00 h for mRNA, and minimum expression at 01:00 and 09:00 h, respectively. We also analyzed CB1R protein and mRNA levels in the pons of rats deprived of total sleep for 24 h and in rats with a 24-h period of sleep deprivation plus a 2-h period of sleep rebound. Unlike sleep deprivation, sleep rebound significantly increased CB1R protein while decreasing mRNA. Despite the fact that we used gentle manipulation to deprive the animals of sleep, there may be a potential influence of stress on this effect, too. However, these facts suggest that CB1R gene expression is modulated by the light/dark cycle and by sleep.

Animals↗
PubMed1995

Role of cyclic AMP dependent protein kinase in cannabinoid receptor modulation of potassium "A-current" in cultured rat hippocampal neurons.

Cannabinoid receptor agonists have been previously shown to enhance a potassium A-current (IA) in cultured rat hippocampal neurons. This effect has been further demonstrated to be dependent on G-protein linkage to adenylyl cyclase and levels of intracellular cyclic AMP (cAMP). The present study extends this analysis to the involvement of cAMP-dependent protein kinase (PKA) in this cascade. Specific activators and inhibitors of PKA were shown to have differential effects on the voltage dependence of IA. Specific activators of PKA produced a negative shift in voltage dependence of IA, whereas PKA inhibitors produced a positive shift in IA voltage dependence, the latter similar to that effected by the cannabinoid agonist WIN 55,212-2. Although the negative shift in IA induced by PKA stimulation could be reversed by PKA inhibitors, the positive shift produced by the PKA inhibitors alone was only 50-60% of the cannabinoid-produced shift in IA voltage dependence. This partial effect of PKA inhibition was confirmed by biochemical assays in the same cultured neurons that showed a similar 50-60% decrement in in vitro protein phosphorylation produced by PKA inhibitors. Results are discussed in terms of a diffusible second messenger linkage of the cannabinoid receptor to the A-current channel via the role of protein phosphorylation in modulation of IA.

Animals↗
PubMedDate not supplied

CB1 cannabinoid receptors modulate kinase and phosphatase activity during extinction of conditioned fear in mice.

Cannabinoid receptors type 1 (CB1) play a central role in both short-term and long-term extinction of auditory-cued fear memory. The molecular mechanisms underlying this function remain to be clarified. Several studies indicated extracellular signal-regulated kinases (ERKs), the phosphatidylinositol 3-kinase with its downstream effector AKT, and the phosphatase calcineurin as potential molecular substrates of extinction behavior. To test the involvement of these kinase and phosphatase activities in CB1-dependent extinction of conditioned fear behavior, conditioned CB1-deficient mice (CB1(-/-)) and wild-type littermates (CB1(+/+)) were sacrificed 30 min after recall of fear memory, and activation of ERKs, AKT, and calcineurin was examined by Western blot analysis in different brain regions. As compared with CB1(+/+), the nonreinforced tone presentation 24 h after auditory-cued fear conditioning led to lower levels of phosphorylated ERKs and/or calcineurin in the basolateral amygdala complex, ventromedial prefrontal cortex, dorsal hippocampus, and ventral hippocampus of CB1(-/-). In contrast, higher levels of phosphorylated p44 ERK and calcineurin were observed in the central nucleus of the amygdala of CB1(-/-). Phosphorylation of AKT was more pronounced in the basolateral amygdala complex and the dorsal hippocampus of CB1(-/-). We propose that the endogenous cannabinoid system modulates extinction of aversive memories, at least in part via regulation of the activity of kinases and phosphatases in a brain structure-dependent manner.

1-Phosphatidylinositol 4-Kinase↗
PubMed2000

Protein kinase-dependent phosphorylation and cannabinoid receptor modulation of potassium A current (IA) in cultured rat hippocampal neurons.

The potent cannabinoid receptor agonist WIN 55,212-2 produces positive shifts in steady-state inactivation of the potassium A current (IA) in rat hippocampal neurons via an adenosine 3',5'-cyclic monophosphate (cAMP)-, protein kinase A (PKA)-dependent process. This effect is probably mediated by phosphorylation or dephosphorylation of the IA channel protein. The role of protein phosphorylation in this cascade was tested by testing cannabinoid actions in cultured hippocampal neurons (pyramidal cells) that were exposed also to either the catalytic subunit of PKA (PKAc), a PKA-specific phosphorylation inhibitor (IP-20, Walsh peptide), or a potent protein phosphatase inhibitor (okadaic acid). Cannabinoids such as WIN 55,212-2 produce a positive (rightwards) shift in the steady-state inactivation of IA, thus providing increased current at a given membrane voltage. Cells dialyzed with PKAc showed a negative shift in IA inactivation, opposite to that produced by cannabinoids, and similar to that produced by increased levels of cAMP. In addition, PKAc completely blocked the positive shift produced by WIN 55,212-2. In contrast, dialysis of cells with IP-20 produced a positive shift in steady state inactivation of IA, similar to that produced by WIN, but the effects were not additive with cannabinoid receptor activation. The phosphatase inhibitor, okadaic acid produced a small negative shift in IA steady-state inactivation when administered alone, and blocked the positive shift produced by WIN 55,212-2. Okadaic acid also enhanced the negative shift in IA inactivation when co-administered with forskolin. The effects of okadaic acid and WIN 55,212-2 were not additive, suggesting a common pathway. These results demonstrate that IA is altered by direct manipulations of the phosphorylation status of the channel protein, and that cannabinoid effects on IA are probably mediated by dephosphorylation of the IA channel.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2005

Species and strain differences in the expression of a novel glutamate-modulating cannabinoid receptor in the rodent hippocampus.

A novel, non-CB1 cannabinoid receptor has been defined by the persistence of inhibition of glutamatergic EPSPs by the cannabinoid receptor agonist WIN55,212-2 in mice lacking the cloned CB1 receptor (CB1-/-) (Hajos et al., 2001). This novel receptor was also distinguished from CB1 by its sensitivity to the antagonist SR141716A and its insensitivity to the antagonist AM251 (Hajos & Freund, 2002). We have chosen to refer to this putative receptor as CBsc due to its identification on Schaffer collateral axon terminals in the hippocampus. We examined properties of CBsc receptors in Sprague Dawley (SD) rats and two strains of wild-type (WT) mice (C57BL/6J and CD1) used as backgrounds for two independent lines of CB1-/- mice (Ledent et al., 1999; Zimmer et al., 1999). The inhibition of synaptic glutamate release by WIN55,212-2 was observed in hippocampal slices from WT CD1 mice and SD rats but was absent in WT C57 mice. We also found that AM251 and SR141716A antagonized the effect of WIN55,212-2 in hippocampal slices from CD1 mice and SD rats demonstrating a lack of selectivity of these ligands for CB1 and CBsc receptors in these animals. The results indicate that the glutamate-modulating CBsc cannabinoid receptor is present in the hippocampi of CD1 mice and SD rats but not in C57BL/6J mice. Thus, we have identified animal models that may permit the study of cannabinoids independently of the novel CBsc receptor (C57CB1+/+), the CBsc receptor independently of the cloned CB1 receptor (CD1CB1-/-), or in the absence of both receptors (C57CB1-/-).

Adenosine↗
PubMed1996

Rat brain cannabinoid receptor modulates N-type Ca2+ channels in a neuronal expression system.

Modulation of neuronal ion channels by the cloned rat brain CB1 cannabinoid receptor was investigated with the use of a heterologous neuronal expression system. Transient expression of the rat brain CB1 cannabinoid receptor was accomplished through microinjection of in vitro transcribed cRNA into the cytoplasm of enzymatically dissociated adult rat superior cervical ganglion neurons. The cannabimimetic aminoalkylindole WIN 55,212-2 inhibited whole-cell Ca2+ currents in neurons injected 16-25 hr previously with rat brain CB1 cannabinoid receptor cRNA. Inhibition of the Ca2+ current was voltage and concentration dependent, with a maximal inhibition of 73% and an IC50 value of 47 nM. The synthetic cannabinoid analogue CP55,940 also inhibited Ca2+ currents, with a maximal inhibition of 38% and an IC50 value of 7 nM. Ca2+ current inhibition was blocked by inclusion of guanosine-5'-O-(2-thiodiphosphate) in the intracellular patch pipette solution or by pretreatment with pertussis toxin. Pretreatment with the N-type Ca2+ channel antagonist omega-conotoxin GVIA reduced the inhibition by 100 nM WIN 55,212-2 from 44% to 6%, indicating that N-type Ca2+ channels are a target of cannabinoid action. On washout of WIN 55,212-2, the Ca2+ current amplitude "overrecovered" in 47% of the neurons tested. Anandamide, the endogenous cannabimimetic compound, had an inconsistent effect on the voltage-dependent Ca2+ currents in the majority of neurons microinjected with cannabinoid receptor cRNA. Ca2+ channels were a specific effector target of the cannabinoid receptor, as two different K+ currents, the M current and the A current, were not modulated by the cannabimimetic WIN 55,212-2.

Animals↗
PubMed2002

C-3 Amido-indole cannabinoid receptor modulators.

C-3 Amido-indoles were found to selectively bind to the CB2 receptor. SAR studies led to optimized compounds with excellent in vivo potency against LPS induced TNF-alpha release in murine models of cytokine production.

Amides↗
PubMed2005

The therapeutic potential of drugs that target cannabinoid receptors or modulate the tissue levels or actions of endocannabinoids.

There are at least 2 types of cannabinoid receptor, CB(1) and CB(2), both G protein coupled. CB(1) receptors are expressed predominantly at nerve terminals and mediate inhibition of transmitter release, whereas CB(2) receptors are found mainly on immune cells, their roles including the modulation of cytokine release and of immune cell migration. Endogenous agonists for cannabinoid receptors also exist. These "endocannabinoids" are synthesized on demand and removed from their sites of action by cellular uptake and intracellular enzymic hydrolysis. Endocannabinoids and their receptors together constitute the endocannabinoid system. This review summarizes evidence that there are certain central and peripheral disorders in which increases take place in the release of endocannabinoids onto their receptors and/or in the density or coupling efficiency of these receptors and that this upregulation is protective in some disorders but can have undesirable consequences in others. It also considers therapeutic strategies by which this upregulation might be modulated to clinical advantage. These strategies include the administration of (1) a CB(1) and/or CB(2) receptor agonist or antagonist that does or does not readily cross the blood brain barrier; (2) a CB(1) and/or CB(2) receptor agonist intrathecally or directly to some other site outside the brain; (3) a partial CB(1) and/or CB(2) receptor agonist rather than a full agonist; (4) a CB(1) and/or CB(2) receptor agonist together with a noncannabinoid, for example, morphine or codeine; (5) an inhibitor or activator of endocannabinoid biosynthesis, cellular uptake, or metabolism; (6) an allosteric modulator of the CB(1) receptor; and (7) a CB(2) receptor inverse agonist.

Animals↗
PubMed2006

The agonists for nociceptors are ubiquitous, but the modulators are specific: P2X receptors in the sensory neurons are modulated by cannabinoids.

P2X2 and P2X3 receptors expressed in mammalian sensory neurons participate in nociception. Cannabinoid receptors modulate nociceptive processing in various models of pain. They are also expressed in nociceptive sensory neurons. We have examined the effect of cannabinoids on the slow P2X2 and P2X2/3 receptors in the cells isolated from nodosal and dorsal root ganglia of rat. The study was carried out by means of the whole-cell patch clamp and rapid superfusion methods. We have found that both endogenous and synthetic cannabinoids (anandamide, WIN55,212-2, and (R)-(+)-methanandamide) inhibit the slow response to ATP mediated by P2X2 and P2X2/3 receptors in a majority of tested neurons. This inhibition was significant but only partial: anandamide (0.5-1 microM) inhibited the response to 51+/-21% of control. In the remaining minority of tested neurons, the response was transiently facilitated. The effect of cannabinoids appears to be mediated via cannabinoid CB(1) receptors: it was reversibly inhibited by selective CB(1) antagonist, SR141716A (10 microM). Introduction of cyclic AMP (0.5 mM) into the cell potently facilitated the inhibitory effect of cannabinoids: the ATP-activated current was inhibited to 13+/-10% of control. These data indicate that cannabinoids may inhibit nociceptive responses produced by P2X receptors.

Adenosine Triphosphate↗
PubMed1999

Cannabinoid receptors differentially modulate potassium A and D currents in hippocampal neurons in culture.

Cannabinoid (CB(1)) receptor activation produced differential effects on voltage-gated outward potassium currents in whole-cell recordings from cultured (7-15 days) rat hippocampal neurons. Voltage-dependent potassium currents A (I(A)) and D (I(D)) were isolated from a composite tetraethylammonium-insensitive current (I(comp)) by blockade with either 4-aminopyridine (500 microM) or dendrotoxin (2 microM) and subtraction of the residual I(A) from I(comp) to reveal I(D). The time constants of inactivation (tau) of I(A) and I(D) as determined in this manner were found to be quite different. The CB(1) agonist WIN 55,212-2 produced a 15- to 20-mV positive shift in voltage-dependent inactivation of I(A) and a simultaneous voltage-independent reduction in the amplitude of I(D) in the same neurons. The EC(50) value for the effect of WIN 55,212-2 on I(D) amplitude (13.9 nM) was slightly lower than the EC(50) value for its effect on I(A) voltage dependence (20.6 nM). Pretreatment with either the CB(1) antagonist SR141716A or pertussis toxin completely blocked the differential effects of WIN 55,212-2 on I(A) and I(D), whereas cellular dialysis with guanosine-5'-O-(3-thio)triphosphate mimicked the action of cannabinoids but blocked the action of simultaneously administered cannabinoid receptor ligands. Finally, the differential effects of cannabinoids on I(A) and I(D) were both shown to be mediated via the well documented cannabinoid receptor inhibition of adenylyl cyclase and subsequent modulation of cAMP and protein kinase. These actions are considered in terms of cAMP-mediated phosphorylation of separate I(A) and I(D) channels and the contribution of each to composite voltage-gated potassium currents in these cells.

4-Aminopyridine↗
PubMed2002

Ethanol, endocannabinoids, and the cannabinoidergic signaling system.

This article represents the proceedings of a symposium at the 2001 annual meeting of the Research Society on Alcoholism in Montreal, Canada. The chairpersons were Appa Hungund and George Koob. The presentations were (1) Role of endocannabinoids in ethanol tolerance, by Appa Hungund; (2) Modulation of cannabinoid receptor and its signal transduction in chronic alcoholism, by B. S. Basavarajappa; (3) Endocannabinoid involvement in the control of appetitive behavior, by George Kunos; (4) Regulation of voluntary ethanol intake by cannabinoid receptor agonists and antagonists in alcohol-preferring sP rats, by Giancarlo Colombo; (5) Role of endogenous cannabinoid system in alcoholism, by Fernado Rodriguez de Fonseca; and (6) Endocannabinoids and dopamine interactions in vivo, by Loren Parsons and George Koob.

Alcoholism↗
PubMed2006

Cannabinoid receptor CB2 modulates the CXCL12/CXCR4-mediated chemotaxis of T lymphocytes.

Cannabinoids have been shown to influence the immune system. However, their immunomodulatory effects have not been extensively studied. In this investigation, we have observed that both primary and Jurkat T cells express a functional cannabinoid receptor 2 (CB(2)). Furthermore, both the synthetic cannabinoids CP55,940 and WIN55,212-2, as well as the CB(2)-selective agonist JWH-015, caused a significant inhibition of the chemokine CXCL12-induced and CXCR4-mediated chemotaxis of Jurkat T cells, as well as their transendothelial migration. Involvement of the CB(2) receptor was further confirmed by partial reversal of the inhibition using the CB(2)-specific antagonist, AM630. Similarly, CP55,940 and JWH-015 inhibited the CXCL12-induced chemotaxis of primary CD4(+) and CD8(+) T lymphocytes. Further investigation of signaling studies to delineate the mechanism of inhibition revealed that cannabinoids enhance CXCL12-induced p44/42 MAP kinase activity. However, enhanced MAP kinase activity was not responsible for the inhibition of chemotaxis. This suggests that cannabinoids differentially regulate CXCR4-mediated migration and MAP kinase activation in T cells. Cannabinoids were also found to downregulate the PMA-enhanced enzyme activity of matrix metalloproteinase-9, which is known to play an important role in transendothelial migration. This study provides novel information regarding cannabinoid modulation of functional effects in T cells.

Calcium↗
PubMed2005

Ethanol desensitizes cannabinoid CB1 receptors modulating monoamine synthesis in the rat brain in vivo.

The endocannabinoid system and the cannabinoid CB(1) receptors are involved in the development of ethanol tolerance and dependence. This study aimed to investigate the in vivo sensitivity of a CB(1) receptor agonist (WIN 55,212-2) modulating the synthesis of 3,4-dihydroxy-phenylalanine/dopamine/noradrenaline (DOPA/DA/NA) and that of 5-hydroxy-tryptophan/serotonin (5-HTP/5-HT) in rat brain after ethanol treatment and withdrawal. In control rats, WIN 55,212-2 (4 mg/kg, i.p., for 1h), through a mechanism sensible to the CB(1) antagonist SR 141716A, increased the synthesis of DOPA/NA in a slice of brainstem containing the locus ceruleus (250%) and in the hippocampus (64%), and it reduced DOPA/DA synthesis in the striatum (47%). WIN 55,212-2 also decreased the synthesis of 5-HTP/5-HT in the locus ceruleus (43%), hippocampus (35%) and striatum (35%). In the locus ceruleus of ethanol-treated rats, the stimulatory effect of WIN 55,212-2 on DOPA/NA synthesis was abolished (acute treatment) or markedly attenuated (53-55%, chronic treatment and withdrawal), whereas in the hippocampus this effect was reduced only in chronic ethanol-withdrawn rats (33%). In the striatum of ethanol-treated rats (acute, chronic and withdrawal), the inhibitory effect of WIN 55,212-2 on DOPA/DA synthesis was completely blunted or markedly reduced. Similarly, the inhibitory effect of WIN 55,212-2 on 5-HTP/5-HT synthesis was reduced or abolished in the three brain regions after chronic ethanol and during withdrawal. These results indicate that treatment with ethanol in rats induces a functional desensitization of CB(1) receptors modulating the synthesis of brain monoamines.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

GABAA receptors modulate cannabinoid-evoked hypothermia.

Cannabinoids evoke hypothermia by stimulating central CB(1) receptors. GABA induces hypothermia via GABA(A) or GABA(B) receptor activation. CB(1) receptor activation increases GABA release in the hypothalamus, a central locus for thermoregulation, suggesting that cannabinoid and GABA systems may be functionally linked in body temperature regulation. We investigated whether GABA receptors modulate the hypothermic actions of [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one] (WIN 55212-2), a selective cannabinoid agonist, in male Sprague-Dawley rats. WIN 55212-2 (2.5 mg/kg im) produced a rapid hypothermia that peaked 45-90 min postinjection. The hypothermia was attenuated by bicuculline (2 mg/kg ip), a GABA(A) antagonist. However, SCH 50911 (1-10 mg/kg ip), a GABA(B) blocker, did not antagonize the hypothermia. Neither bicuculline (2 mg/kg) nor SCH 50911 (10 mg/kg) by itself altered body temperature. We also investigated a possible role for CB(1) receptors in GABA-generated hypothermia. Muscimol (2.5 mg/kg ip), a GABA(A) agonist, or baclofen (5 mg/kg ip), a GABA(B) agonist, evoked a significant hypothermia. Blockade of CB(1) receptors with SR141716A (2.5 mg/kg im) did not antagonize muscimol- or baclofen-induced hypothermia, indicating that GABA-evoked hypothermia does not contain a CB(1)-sensitive component. Our results implicate GABA(A) receptors in the hypothermic actions of cannabinoids and provide further evidence of a functional link between cannabinoid and GABA systems.

Animals↗
PubMed2005

CB(1) cannabinoid receptor stimulation modulates transient receptor potential vanilloid receptor 1 activities in calcium influx and substance P Release in cultured rat dorsal root ganglion cells.

Cannabinoids have been reported to have analgesic properties in animals of acute nociception or of inflammatory and neuropathic pain models, but the mechanisms by which they exert such alleviative effects are not yet fully understood. We investigated whether the CB(1)-cannabinoid-receptor agonist HU210 modulates the capsaicin-induced (45)Ca(2+) influx and substance P like-immunoreactivity (SPLI) release in cultured rat dorsal root ganglion (DRG) cells. HU210 attenuated the capsaicin-induced (45)Ca(2+) influx and this effect was reversed by the CB(1) antagonist AM251. Treatment of DRG cells with 100 nM bradykinin for 3 h potentiated capsaicin-induced SPLI release accompanied with the induction of cyclooxygenase-2 mRNA expression. The potentiation of SPLI release by bradykinin was reversed by HU210 or the protein kinase A (PKA) inhibitor H-89. HU210 also reduced forskolin-induced cyclic AMP production and forskolin-induced potentiation of SPLI release. These results suggest that CB(1) could inhibit either the capsaicin-induced Ca(2+) influx or the potentiation of capsaicin-induced SPLI release by a long-term treatment with bradykinin through involvement of a cyclic-AMP-dependent PKA pathway. In conclusion, CB(1)-receptor stimulation modulates the activities of transient receptor potential vanilloid receptor 1 in cultured rat DRG cells.

Animals↗
PubMed1990

Cannabinoid receptors and modulation of cyclic AMP accumulation in the rat brain.

The mechanism by which cannabinoid compounds produce their effects in the rat brain was evaluated in this investigation. Cannabinoid receptors, quantitated by [3H]CP-55,940 binding, were found in greatest abundance in the rat cortex, cerebellum, hippocampus, and striatum, with smaller but significant binding also found in the hypothalamus, brainstem, and spinal cord. Using rat brain slice preparations, we evaluated the effect of desacetyllevonantradol on basal and forskolin-stimulated cyclic AMP accumulation in the regions exhibiting the greatest cannabinoid receptor density. Desacetyllevonantradol (10 microM) reduced cyclic AMP levels in the hippocampus, frontal cortex, and striatum. In the cerebellum, however, the response to desacetyllevonantradol was biphasic with cyclic AMP accumulation being decreased at lower and increased at higher concentrations. Desacetyllevonantradol reduced cyclic AMP accumulation in isoproterenol-stimulated slices in the cortex and cerebellum, but not in the hippocampus. Cells that responded to vasoactive intestinal peptide with an increase in cyclic AMP accumulation in the hippocampus and cortex also responded to desacetyllevonantradol. The modulation of cyclic AMP accumulation by desacetyllevonantradol could be attenuated following stereotaxic implantation of pertussis toxin, supporting the involvement of a G protein in the cannabinoid response in the brain. However, other actions of cannabinoid compounds may also affect the cyclic AMP levels in brain slice preparations.

Analgesics↗