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PubMed1979

Effects of cannabinoids on testosterone and protein synthesis in rat testis Leydig cells in vitro.

Various water-insoluble cannabinoids as well as SP-111A, the water-soluble derivative of delta 9-tetrahydrocannabinol (delta 9-THC), reduced hCG and dibutyryl-cAMP stimulated testosterone production by rat testicular Leydig cell preparations. With 0.15 microM (0.05 micrograms/ml) 8-beta-OH-delta 9-THC the inhibition was about 50% of stimulated testosterone synthesis. Dose-related inhibitions were apparent with other cannabinoids and their order of potency in inhibiting stimulated steroidogenesis by the interstitial cells in vitro was found to be: 8-beta-OH-delta 9-THC greater than or equal to 11-OH-delta 9-THC greater than CBN = CBD = CBG greater than or equal delta 9-THC = delta 8-THC. The non-stimulated, basal, steroidogenesis was not affected even with 15 microM cannabinoids. The incorporation of L-[U-14C]leucine into the protein of Leydig cells was markedly reduced by 15 microM cannabinoids under both basal and stimulated conditions. The inhibition of steroidogenesis as well as protein synthesis in rat testicular Leydig cell preparations by various cannabinoids cannot be correlated with their psychoactivity. The present data suggest that cannabinoids at very low concentrations may interfere directly in Leydig cells with both protein and testosterone synthesis, and thus with their function.

Animals↗
PubMed2006

Adolescent exposure to nicotine modifies acute functional responses to cannabinoid agonists in rats.

We have studied functional interactions between nicotine and the cannabinoid receptor agonist CP 55,940 (CP) in the modulation of behavioural and corticosterone responses of male and female adolescent Wistar rats. The animals underwent a subchronic nicotine treatment (0.4 mg/kg i.p., once daily) during the periadolescent period (postnatal days 34-43). Twenty-four hours after the last injection of nicotine an acute dose of CP (1 or 100 microg/kg i.p.) was administered. Thirty minutes after the cannabinoid injection, the animals were tested individually in the holeboard immediately followed by the elevated plus-maze. We also measured corticosterone levels by radioimmunoassay. In males, neither CP (1 microg/kg) nor nicotine induced any modification in anxiety when administered alone. However, the combination of the two drugs resulted in a significant anxiogenic-like effect. In females, the lower dose of CP was anxiogenic and nicotine, which did not induce any effect per se, prevented this response. In the holeboard, subchronic nicotine and the acute cannabinoid treatment interacted in the modulation of horizontal activity and the nature of this interaction also showed a clear sexual dimorphism. Both, the cannabinoid agonist and nicotine increased corticosterone concentrations and the animals receiving the two drugs showed higher levels than the animals receiving the cannabinoid alone. The data provide evidence for the existence of functional interactions between nicotine and cannabinoids in the modulation of behavioural responses and adrenocortical activity in adolescent rats.

Adrenal Cortex↗
PubMed2004

Expression and biological effects of CB1 cannabinoid receptor in rat parotid gland.

Experiments were designed to determine whether cannabinoids affect salivary gland function. For this purpose, the effect of anandamide on cAMP accumulation, amylase release and Na+-K+-ATPase activity was studied in rat parotid glands. Anandamide induced a concentration-dependent increase in cAMP and led to amylase release but inhibited Na+-K+-ATPase activity. These effects were blocked by the CB1 cannabinoid receptor antagonist, AM281. The inhibition of adenylyl cyclase activity by SQ 22536 impaired amylase release and Na+-K+-ATPase inhibition. The effect of anandamide on cAMP accumulation significantly correlated with its action either on amylase release or on Na+-K+-ATPase activity. Such correlation strongly supports the view that the effect of anandamide on amylase release and Na+-K+-ATPase activity is the result of cAMP accumulation. The relative potencies of the CB1 cannabinoid receptor antagonist, AM281, to block these three functional responses were similar, supporting the view that anandamide actions in parotid glands were achieved through a single receptor subtype, the CB1. Binding studies using the selective cannabinoid CB1 receptor antagonist, [3H]SR141716A, indicated the presence of the specific binding site. It may be concluded that in parotid glands the endogenous cannabinoid anandamide, bound to the CB1 cannabinoid receptor subtype, induces cAMP accumulation which in turn leads to amylase release and Na+-K+-ATPase inhibition.

Animals↗
PubMed2004

6"-Azidohex-2"-yne-cannabidiol: a potential neutral, competitive cannabinoid CB1 receptor antagonist.

Previous experiments with the mouse vas deferens have shown that cannabidiol produces surmountable antagonism of cannabinoid CB(1) receptor agonists at concentrations well below those at which it binds to cannabinoid CB(1) receptors and antagonizes alpha(1)-adrenoceptor agonists insurmountably. It also enhances electrically evoked contractions of this tissue. We have now found that subtle changes in the structure of cannabidiol markedly influence its ability to produce each of these effects, suggesting the presence of specific pharmacological targets for this non-psychoactive cannabinoid. Our experiments were performed with cannabidiol, 6"-azidohex-2"-yne-cannabidiol, abnormal-cannabidiol and 2'-monomethoxy- and 2',6'-dimethoxy-cannabidiol. Of these, 6"-azidohex-2"-yne-cannabidiol was as potent as cannabidiol in producing surmountable antagonism of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (R-(+)-WIN55212) in vasa deferentia. However, it produced this antagonism with a potency that matched its cannabinoid CB(1) receptor affinity, suggesting that, unlike cannabidiol, it is a competitive cannabinoid CB(1) receptor antagonist. Moreover, since it did not enhance the amplitude of electrically evoked contractions, it may be a neutral cannabinoid CB(1) receptor antagonist.

Adenosine Triphosphate↗
PubMed2005

Suppression of feeding, drinking, and locomotion by a putative cannabinoid receptor 'silent antagonist'.

This study compared the effects of the putative cannabinoid receptor 'silent antagonist' O-2050 with the cannabinoid receptor inverse agonist SR 141716 on food and water consumption, and locomotor activity. Non-deprived male Wistar rats were habituated to the apparatus and testing procedures, then injected intraperitoneally with vehicle, O-2050 (0.03-3.0 mg/kg), or SR 141716 (3.0 mg/kg) prior to 4-h test sessions. Food consumption was significantly reduced by both drugs. Water intake and locomotor activity were significantly reduced only by O-2050. Results support the notion that cannabinoid receptor antagonists suppress feeding behaviour by blocking an endogenous cannabinoid orexigenic signal, rather than by inverse agonism at cannabinoid receptors. However, further studies are needed to confirm the status of O-2050 as a cannabinoid CB(1) receptor antagonist devoid of inverse agonist properties.

Animals↗
PubMed2006

Subchronic nicotine exposure in adolescence induces long-term effects on hippocampal and striatal cannabinoid-CB1 and mu-opioid receptors in rats.

There is evidence for the existence of functional interactions between nicotine and cannabinoids and opioid compounds in adult experimental animals. However, there is scarce information about these relationships in young animals. In the present study we evaluated short and long-term effects of a subchronic nicotine treatment [0.4 mg/kg daily i.p. injections from postnatal day (PND) 34 to PND 43], upon hippocampal and striatal cannabinoid-CB(1) and mu-opioid receptors in Wistar rats of both genders. Rats were sacrificed 2 h after the last nicotine injection (short-term effects, PND 43) or one month later (long-term effects, PND 75). Hippocampal and striatal cannabinoid CB(1) and mu-opioid receptors were quantified by Western blotting. The subchronic nicotine treatment induced a region-dependent long-lasting effect in cannabinoid CB(1) receptor: a significant increase in hippocampal cannabinoid CB(1) receptors and a significant decrease in striatal cannabinoid CB(1) receptors, with these effects being similar in males and females. With respect to mu-opioid receptors, subchronic nicotine induced a significant down-regulation in hippocampal and striatal mu-opioid receptors in the long-term, and within the striatum the effects were more marked in adult males than in females. The present results indicate that juvenile nicotine taking may have implications for the endocannabinoid and endogenous opioid function and for the behaviors served by those systems, this includes possible modification of the response of adults to different psychotropic drugs, i.e. cannabis and morphine/heroin when taken later in life.

Animals↗
PubMed2006

Involvement of cannabinoid CB2 receptors in the IgE-mediated triphasic cutaneous reaction in mice.

Involvement of cannabinoid CB2 receptors in the IgE-mediated cutaneous reaction was investigated. Epicutaneous challenge with 2,4-dinitrofluorobenzene caused a triphasic swelling in the ear of BALB/c and C57BL/6 mice passively sensitized with anti-dinitrophenol IgE. Peak responses of the ear swelling appeared at 1 h, 24 h, and 8 days after the challenge in both strains of mice. In contrast, cannabinoid CB2 receptor-deficient mice failed to exhibit the obvious triphasic ear swelling observed in wild-type mice. Oral administration of cannabinoid CB2 receptor antagonist/inverse agonists [N-(benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide] (JTE-907) and {N-[(1S)-endo-1,3,3-trimethylbicyclo[2,2,1]heptan-2yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide} (SR144528) at doses of 0.1-10 mg/kg significantly and dose-dependently suppressed all three phases of ear swelling in BALB/c mice. Interestingly, epicutaneous treatment with an ether-linked analogue of endogenous cannabinoids, 2-arachidonoylglycerol, caused an ear swelling that could be detected at 1 h, 24 h, and 8 days after treatment of both BALB/c and C57BL/6 mice. These results suggest that cannabinoid CB2 receptors are involved in induction of the triphasic cutaneous reaction mediated by IgE, and that cannabinoid CB2 receptor antagonist/inverse agonists may serve as anti-allergic agents in the treatment of allergic dermatitis.

Animals↗
PubMed2004

The cannabinoid dexanabinol is an inhibitor of the nuclear factor-kappa B (NF-kappa B).

Exogenous and endogenous cannabinoids have been shown to have neuroprotective effects in vitro and in vivo. Although many of the pharmacological effects of cannabinoids have been identified, the mechanism of neuroprotection still represents a controversy. Here we demonstrate for the first time protective effects of the synthetic cannabinoid dexanabinol by inhibiting apoptosis in a neuron-like cell line using nuclear staining and FACS analysis and in primary neurons. We provide further evidence of inhibition of nuclear factor-kappakappa B (NF-kappaB) by dexanabinol: Dexanabinol inhibits (1) phosphorylation and degradation of the inhibitor of NF-kappaB IkappaBalpha and translocation of NF-kappaB to the nucleus; dexanabinol reduces (2) the transcriptional activity of NF-kappaB and (3) mRNA accumulation of the NF-kappaB target genes tumor necrosis factor-alpha and interleukin-6 (TNF-alpha and IL-6). Dexanabinol does not bind to cannabinoid (CB) receptors 1 and 2. To investigate the mechanism of action, we employed the non-antioxidant CB1 receptor agonist WIN 55,212-2 and the antioxidant cannabinol, which binds to CB1 receptors only weakly. Both cannabinoids mimicked the effect of dexanabinol on NF-kappaB and apoptosis. This suggests that neither the antioxidant properties of cannabinoids nor binding to CB1 or CB2 receptors are responsible for the inhibition of NF-kappaB activity and apoptosis. Our results clearly demonstrate that dexanabinol inhibits NF-kappaB. NF-kappaB has been shown to be involved in brain damage and to promote neuronal cell death in vitro and in in vivo models of ischemic and neurodegenerative neurological diseases.

Animals↗
PubMed2004

Evidence for an interaction between CB1 cannabinoid and oxytocin receptors in food and water intake.

Oxytocin and CB(1) cannabinoid receptors independently modulate food intake. Although an interaction between oxytocin and cannabinoid systems has been demonstrated with respect to the cannabinoid withdrawal syndrome, the interaction between these systems in modulating food intake has not yet been examined. The present study had three primary purposes: (1) to determine whether oxytocin and a CB(1) receptor antagonist block food and fluid intake in a supra-additive manner, (2) to determine the relative position of the CB(1) receptors in the chain of control of food intake in relation to the oxytocin system, and (3) to determine whether the increase in fluid intake induced by an oxytocin antagonist is mediated via cannabinoid receptors. Rats were habituated to the test environment and injection procedure, and then received intracerebroventricular (ICV) injections of various combinations of the oxytocin receptor antagonist tocinoic acid, the cannabionid receptor agonist delta(9)-tetrahydrocannabinol (THC), oxytocin, or the cannabinoid receptor antagonist SR 141716. Food and water intake and locomotor activity were then measured for 120 min. When administrated alone, SR 141716 and oxytocin dose-dependently attenuated baseline food intake, while oxytocin but not SR 141716 reduced water intake. Sub-anorectic doses of SR 141716 and oxytocin attenuated baseline feeding beyond what would be expected by the sum of the individual drug effects without affecting baseline water intake. THC stimulated feeding but not water intake. THC-induced feeding was not blocked by oxytocin, however, the oxytocin did attenuate water intake during such feeding. SR 141716 dose-dependently reduced tocinoic-acid-stimulated food intake and partially attenuated water intake. Locomotor activity was not significantly affected by any drug treatments, suggesting that effects on feeding were not due to a non-specific reduction in motivated behaviour. These findings reveal an interaction between cannabinoid and oxytocin systems in food intake. Results further reveal that the oxytocin system effects on water intake are partially mediated via CB(1) receptors, CB(1) receptors are located downstream from oxytocin receptors, and CB(1) receptor signalling is necessary to prevent oxytocin from altering food intake.

Animals↗
PubMed2006

Strain and schedule-dependent differences in the acquisition, maintenance and extinction of intravenous cannabinoid self-administration in rats.

Cannabinoids have been reported to sustain self-administration in laboratory animals; however, genetic differences and environmental factors critical in the initiation and retention of such behaviour are yet to be defined. This study investigated the acquisition, maintenance and extinction of self-administration of the cannabinoid CB1 receptor agonist WIN 55,212-2 (6.25-25 microg/kg/inf) in Long Evans, Lister Hooded and Sprague-Dawley rats under a continuous schedule of reinforcement and two different response-like operanda, nose-poking and lever-pressing. Results showed that Long Evans and Lister Hooded, but not Sprague Dawley, rats acquired and retained stable cannabinoid self-administration behaviour under both modus operandi, as defined by significant differences between responding in the active versus the inactive hole/lever. In rats developing firm self-administration, substitution of saline for WIN 55,212-2 extinguished the responding, supporting the notion that cannabinoids may serve as a positive reinforcer in laboratory animals. Nevertheless, significant differences among strains and responding modalities were observed in the percentage of acquisition, amount of drug intake during maintenance and timing of extinction. In addition, no significant strain differences were found in motor response to WIN 55,212-2 (0.3 and 3.0 mg/kg), thus excluding that strain differences observed during cannabinoid self-administration could be related to different cannabinoid-induced locomotor effects.

Analgesics↗
PubMed2005

Cannabinoid-receptor 1 null mice are susceptible to neurofilament damage and caspase 3 activation.

Administered cannabinoids have been shown to ameliorate signs of CNS inflammatory disease in a number of animal models, including allergic encephalomyelitis. More recently, neuroprotective actions have been attributed to activation of the cannabinoid 1 receptor in a number of in vitro and in vivo models. One of these, chronic relapsing experimental allergic encephalomyelitis, is considered a robust analog of multiple sclerosis. In this study, spinal cord tissue from cannabinoid receptor 1 knockout mice was analyzed for neurofilament H and myelin basic protein content, as markers of neurons/axons and myelin respectively, during the course of chronic relapsing experimental allergic encephalomyelitis. Dephosphorylation of a neurofilament H epitope, immunoreactive to the SMI32 antibody, was assessed as a marker of axonal damage and levels of the endpoint cell death mediator caspase 3 were evaluated. It was found that both neurofilament and myelin basic protein levels decrease over the course of disease, indicating concomitant neuronal/axonal loss and demyelination. Loss of each marker was more severe in cannabinoid receptor 1 knockout animals. Increased SMI32 reactivity was observed as disease progressed. SMI32 reactivity was significantly increased in knockout animals over wildtype counterparts, an indication of greater axonal dephosphorylation and injury. Active caspase 3 levels were increased in all animals during disease, with knockout animals displaying highest levels, even in knockout animals prior to disease induction. These results indicate that lack of the cannabinoid receptor 1 is associated with increased caspase activation and greater loss and/or compromise of myelin and axonal/neuronal proteins. The increase of caspase 3 in knockout mice prior to disease induction indicates a latent physiological effect of the missing receptor. The data presented further strengthen the hypothesis of neuroprotection elicited via cannabinoid receptor 1 signaling.

Animals↗
PubMed1999

Cannabinoid receptors and their role in the regulation of the serotonin transporter in human placenta.

OBJECTIVE: We sought to investigate the expression of cannabinoid receptors in human placenta and BeWo choriocarcinoma cells and study their role in the regulation of the serotonin transporter. STUDY DESIGN: Expression of the 2 types of cannabinoid receptors (CB1 and CB2) in human placenta and BeWo cells was investigated by reverse transcriptase-polymerase chain reaction and Northern blot analysis. The involvement of the receptors in the regulation of the serotonin transporter expression was studied by using a cannabinoid receptor agonist (WIN 55212-2). BeWo cells were treated with the agonist in the presence or absence of forskolin, and the serotonin transporter activity was measured by assessing paroxetine-sensitive serotonin transport. Serotonin transporter density in cell membranes was monitored by measuring paroxetine-sensitive binding of RTI-55, a specific high-affinity ligand for the transporter. Agonist-induced changes in intracellular levels of cyclic adenosine monophosphate were also monitored. RESULTS: Reverse transcriptase-polymerase chain reaction and Northern blot analysis demonstrated unequivocally that human placenta and BeWo cells express both types of cannabinoid receptors. Treatment of BeWo cells with the receptor agonist blocked the activity of the constitutive, as well as the forskolin-induced, serotonin transporter without affecting the serotonin transporter density. This effect is not mediated by alterations in intracellular cyclic adenosine monophosphate levels. CONCLUSION: The results show that cannabinoid receptors are expressed in human placenta and BeWo cells and play a role in the regulation of the serotonin transporter activity. Human placenta is therefore a direct target for cannabinoids, and marijuana use during pregnancy is likely to affect the placental clearance of serotonin through the serotonin transporter.

Benzoxazines↗
PubMed1997

Interaction of brain cannabinoid receptors with guanine nucleotide binding protein: a radioligand binding study.

The binding of a classical cannabinoid agonist, [3H]R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2 ,3-de]-1,4-benzoxazin-6-yl)(1-napthalenyl)methanone monomethanesulfonate ([3H] WIN55212-2), and a selective cannabinoid receptor (CB1) antagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)1-(2,4-dichlorophenyl)-4-meth yl-1H-pyrazole-3-carboxamide hydrochloride ([3H]SR141716A), to rat cannabinoid receptors was evaluated using rat cerebellar membranes. Guanine nucleotides inhibited [3H]WIN55212-2 binding by approximately 50% at 10 microM and enhanced [3H]SR141716A binding very slightly. In the same tissue, the binding of guanosine 5'-O-[gamma-[35S]thio]triphosphate ([35S]GTP-gamma-S) was characterized and the influence of cannabinomimetics evaluated on this binding. Cannabinoid receptor agonists enhanced [35S]GTP-gamma-S binding, whereas SR141716A was devoid of action by itself but antagonized the action of cannabinoid receptor agonists. The good correlation obtained between the half maximum efficient concentration (EC50) values in [35S]GTP-gamma-S binding and the IC50 values [3H]WIN55212-2 binding shows that [35S]GTP-gamma-S binding could be a good functional assay for brain cannabinoid receptors.

Animals↗
PubMed2003

Effects of neurotoxic destruction of descending noradrenergic pathways on cannabinoid antinociception in models of acute and tonic nociception.

The effects of neurotoxic destruction of catecholaminergic projections to the spinal cord on cannabinoid antinociception were examined in models of acute and tonic nociception. High performance liquid chromatography was used to quantify monoamine levels in sham-operated and lesioned rats. Intrathecal administration of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA) induced a selective depletion of norepinephrine (by approximately 85% of control) in rat lumbar spinal cord without altering levels of dopamine or serotonin. By contrast, brain levels of monoamines did not differ in sham-operated and lesioned rats. Pain behavior was similar in sham-operated and lesioned rats receiving vehicle in models of both acute and tonic nociception. The cannabinoid agonist WIN55,212-2 (5 or 10 mg/kg, i.p.) produced antinociception in the tail-flick test in sham-operated rats. The antinociceptive effect of WIN55,212-2 was attenuated relative to control conditions in rats depleted of spinal norepinephrine. WIN55,212-2 suppressed tonic pain behavior in the formalin test in sham-operated rats during phase 2 (15-60 min post formalin) of nociceptive responding. By contrast, in lesioned rats, WIN55,212-2 suppressed pain behavior during phase 1 (0-9.9 min) and phase 2A (10-39.9 min), but not during phase 2B (40-60 min). The cannabinoid agonist suppressed formalin-evoked Fos protein expression, a marker of neuronal activity, in the lumbar dorsal horn of sham-operated rats, but no suppression was observed in lesioned rats. The number of formalin-evoked Fos-like immunoreactive (FLI) cells was greater in lamina I and II of lesioned rats relative to sham-operated rats. These data indicate that the suppressive effect of the cannabinoid on formalin-evoked Fos protein expression in the superficial dorsal horn was attenuated following destruction of descending noradrenergic pathways. Our data are consistent with the hypothesis that cannabinoids produce antinociception, in part, by modulating descending noradrenergic systems and support a differential involvement of noradrenergic projections to the spinal cord in cannabinoid modulation of acute versus tonic nociception.

Analgesics↗
PubMed2001

The cannabinoid CB1 receptor antagonist SR 141716A reverses the antiemetic and motor depressant actions of WIN 55, 212-2.

The dibenzopyran cannabinoids (delta-9 (Delta9)-tetrahydrocannabinol and nabilone) are clinically used to suppress nausea and vomiting produced by chemotherapeutic agents such as cisplatin. The purpose of this investigation was to investigate the antiemetic potential of the aminoalkylindole cannabinoid receptor agonist WIN 55, 212-2 [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl) methyl] pyrolol [1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl) methanone mesylate] against cisplatin-induced vomiting. Different doses of WIN 55, 212-2 (0, 1, 2.5 and 5 mg/kg, i.p.) reduced both the frequency of cisplatin (20 mg/kg, i.p.)-induced emesis (ID(50)=0.5 mg/kg) as well as the percentage of shrews vomiting (ID50=1.2 mg/kg) in a dose-dependent manner. Significant reductions in emesis frequency occurred from 2.5 mg/kg dose of WIN 55, 212-2, whereas significant total protection from vomiting was afforded at its 5 mg/kg dose. The antiemetic actions of a 5-mg/kg dose of WIN 55, 212-2 against cisplatin (20 mg/kg, i.p.)-induced vomiting were reversed by nonemetic subcutaneous doses (0, 0.25, 0.5 and 1 mg/kg) of the cannabinoid CB1 receptor antagonist/inverse agonist SR 141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] (ID50=0.27 and 0.47 mg/kg, respectively) but not by a 5-mg/kg dose of the cannabinoid CB2 receptor antagonist SR 144528 [N-[(1S)-endo-1,3,3-trimethylbicyclo [2.2.1] heptan-2-yl]5-(4-chloro-3-methylphenyl)-1-(4-methybenzyl) pyrazole-3-carboxamide]. The effects of the cited doses of WIN 55, 212-2 were also investigated on several motor parameters (spontaneous locomotor activity, duration of movement and rearing frequency). Significant reductions in motor parameters were only observed at its highest tested dose (ID50=1.97, 2.75 and 2.8 mg/kg; respectively). SR 141716A (0, 0.5, 1, 5 and 10 mg/kg) also reversed the motor suppressant effects of a 5-mg/kg dose of WIN 55, 212-2 (ID50=0.39, 0.1 and 0.3 mg/kg, respectively) and significant reversals were seen from its 0.5 and 1 mg/kg doses. These results suggest that WIN 55, 212-2 reduces both emesis and indeces of locomotion via the stimulation of cannabinoid CB1 receptors. However, cannabinoid CB1 receptors in different loci are most likely responsible for the antiemetic and motor suppressive effects of WIN 55, 212-2 since reduction in the frequency of vomiting occurred at lower doses relative to its sedative actions.

Animals↗
PubMed2001

Evidence for presynaptic cannabinoid CB(1) receptor-mediated inhibition of noradrenaline release in the guinea pig lung.

Using neurochemical method, evidence was obtained that cannabinoid CB(1) receptors are localized on noradrenergic terminals and their stimulation by WIN-55,212-2 reduces the release of [3H]noradrenaline evoked by axonal activity in a frequency-dependent manner. At stimulation rates of 1 and 3 Hz, there was significant inhibition of noradrenaline release, with IC(50) of WIN-55,212-2 41.5+/-2.6 and 320.5+/-28.2 nM, for 1 and 3 Hz, respectively. Cannabinoid CB(1) receptor antagonist SR 141716A completely prevented WIN-55,212-2 from reducing the release. The release of noradrenaline is negatively modulated by presynaptic alpha(2)-adrenoceptors. Because BRL-44408, an alpha(2B)-adrenoceptor, and prazosin, an alpha(1)- and alpha(2B)-adrenoceptor antagonist, both increased the release of [(3)H]noradrenaline, it seems likely that the alpha(2B) subtype is responsible for the negative feedback modulation of noradrenaline release. In the presence of alpha(2)-adrenoceptor antagonism, cannabinoid CB(1) receptor activation by WIN-55,212-2 was much more effective in inhibiting the release of [(3)H]noradrenaline. Using a specific antibody against the C-terminus of the rat cannabinoid CB(1) receptor and also against neuropeptide Y, ultrastructural evidence was obtained that cannabinoid CB(1) receptors are exclusively localized on neuropeptide Y-positive noradrenergic varicosities. Since the sympathetic innervation of the human airway smooth muscle is sparse, and mainly the circulating adrenaline relaxes the airways via activation of beta(2)-adrenoceptor localized on the smooth muscle, it is suggested that inhibition of noradrenaline release by cannabinoids, and the subsequent bronchospasm, may be limited to those cases when noradrenaline released from sympathetic varicosities is involved in airway relaxation.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1998

Antihyperalgesic effects of spinal cannabinoids.

Cannabinoids have been widely reported to produce antinociception in models such as tail flick and hot plate. However, their role in modulating thermal hyperalgesia is unknown. The potency of some drugs, such as the opioids, increases during hyperalgesia. Thus, we evaluated whether there is a change in the effectiveness of intrathecal cannabinoids with hyperalgesia. Additionally, we evaluated whether cannabinoids could inhibit capsaicin-evoked neurosecretion from isolated rat spinal cord. Our results indicate that 1 fmol anandamide (i.t.) completely blocked carrageenan-induced thermal hyperalgesia. However, anandamide at doses as high as 100 pmol had no effect on thermal latencies in normal animals. Additionally, anandamide inhibited K+- as well as capsaicin-evoked immunoreactive calcitonin gene-related peptide release. Finally, cannabinoid receptors were identified in sensory neurons. Collectively, these results indicate that there is an increased effectiveness of modulation of thermal nociceptive thresholds by spinal cannabinoids during hyperalgesia. This antihyperalgesic effect may be the result of cannabinoid-induced inhibition of neurosecretion from certain primary afferent fibers.

Animals↗
PubMed1998

Local effects of cannabinoids on spontaneous activity and evoked inhibition in the globus pallidus.

The globus pallidus has been identified as a site of action for the motor effects of cannabinoids. A previous report from this laboratory demonstrated that systemic administration of the potent and selective cannabinoid receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl) methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl] (1-napthalenyl) methanone (WIN 55,212-2) inhibits rat pallidal neurons and reverses the inhibition of pallidal activity produced by electrical stimulation of the striatum. The current study used in vivo single unit electrophysiology/micropressure ejection to investigate whether the effects of cannabinoids on spontaneous activity and evoked inhibition in the globus pallidus are locally mediated. Micropressure ejection of either WIN 55,212-2 or CP 55,940 into the globus pallidus inhibited spontaneous activity in the globus pallidus. Local administration of the cannabinoid receptor antagonist, N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazo le-carboxamide (SR141716A), did not produce an effect on its own but blocked the effect of WIN 55,212-2 on spontaneous activity of pallidal neurons. The decrease in pallidal activity produced by WIN 55,212-2 was not blocked by coadministration of bicuculline, suggesting this effect is independent of GABA(A) receptors. Micropressure ejection of cannabinoids into the globus pallidus did not reverse the inhibitory effect of striatal stimulation in the globus pallidus. Taken together, these findings suggest that pallidal cannabinoid receptors mediate an inhibition of spontaneous activity in the globus pallidus.

Animals↗