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PubMed2005

CB1 cannabinoid receptors are enriched in the perisynaptic annulus and on preterminal segments of hippocampal GABAergic axons.

Cannabinoids have been shown to modulate the inhibitory effect of cholecystokinin-containing GABAergic interneurons in the hippocampus via type 1 cannabinoid receptors (CB1 receptor). Although immunohistochemical studies, using pre-embedding techniques, have demonstrated that these receptors are abundant on GABAergic axon terminals, little is known about their exact location relative to the synapse. Here we used two recently developed antibodies against the CB1 receptor to study this question with the postembedding immunogold method, which allows the quantitative examination of receptor distribution along the axonal membrane, even within the synaptic active zone. CB1 receptor positive terminals target both the dendritic and somatic surface of neurons in the CA1 area of the rat hippocampus. We found no difference between these two populations of terminals either in their CB1 receptor density or in the distribution of receptors on their membrane. Recent studies suggest that endocannabinoids play a role in retrograde signaling at these synapses, i.e. signaling molecules diffuse from the postsynaptic membrane to nearby presynaptic terminals. Therefore, we examined the distribution of CB1 receptors on the terminal membranes. We found that they are rare in the synaptic active zone, but are enriched in the perisynaptic annulus, where they can directly influence synaptic calcium channels. Perisynaptic CB1 receptors represent about one tenth of all CB1 receptors in a terminal. In contrast, CB1 receptors have a lower density on the extrasynaptic membrane of terminals far from the postsynaptic cell. We estimated that these terminals contain exceptionally large numbers of CB1 receptors, i.e. a single axon terminal was usually labeled with more than 450 particles. An unexpected finding was that the density of CB1 receptors was significantly higher on preterminal axons than on synaptic terminals. These observations suggest that endocannabinoid signaling may subserve roles other than simply reducing transmitter release from axon terminals.

Animals↗

PubMed1999

Inhibitory effect of cannabinoid agonists on gastric emptying in the rat.

We have studied the effect of WIN 55,212-2 (a psychoactive cannabinoid agonist), cannabinol (a nonpsychoactive cannabinoid agonist), SR141716A, a cannabinoid CB1 antagonist, and SR144528, a cannabinoid CB2 antagonist, on gastric emptying in the rat. WIN 55,212-2 (0.1-5 mg/kg, i.p.) and cannabinol (0.1-25 mg/kg, i.p.) dose-dependently delayed gastric emptying while SR141716A (1 mg/kg and 5 mg/kg) and SR144528 (1 mg/kg) were without effect. SR141716A (1 mg/kg), but not SR144528 (1 mg/kg), counteracted the inhibitory effect of the two cannabinoid agonists. These results suggest that cannabinoid agonists delay gastric emptying through activation of cannabinoid CB1 receptors, while the endogenous cannabinoid system does not seem to modulate gastric motility.

Analgesics↗

PubMed2006

CB1 receptor selective activation inhibits beta-amyloid-induced iNOS protein expression in C6 cells and subsequently blunts tau protein hyperphosphorylation in co-cultured neurons.

Among the wide range of neuro-inflammatory signalling molecules released by beta-amyloid-stimulated astroglial cells, nitric oxide (NO) plays a fundamental role in AD aethiopathogenesis since it directly promotes neuronal tau protein hyperphosphorylation leading to neurofibrillary tangle formation. Synthetic cannabinoids (CBs), via a selective CB1 receptor activation, negatively modulates both iNOS protein expression and NO production induced by pro-inflammatory stimuli. In this study we investigated the role of both the non-selective WIN 55,212-2 and the selective CB1 receptor agonist, ACEA, on: (i) NO production, (ii) iNOS protein expression in (1-42) beta-amyloid peptide (Abeta)-stimulated C6 rat glioma cells and (iii) tau protein hyperphosphorylation in co-cultured differentiated PC12 neurons. Our results demonstrated that synthetic CBs, by a selective CB1 effect, down-regulate iNOS protein expression and NO production in Abeta-stimulated C6 cells. This effect leads, in turn, to a significant and concentration-dependent inhibition of NO-dependent tau protein hyperphosphorylation in co-cultured PC12 neurons. The results of the present study extend our knowledge about the neuroprotective actions of synthetic CBs on Abeta-dependent neurotoxicity in vitro. Furthermore, our study allows us to identify, in the CB1-mediated inhibition of astroglial-derived NO, a new potential target to blunt tau hyperphosphorylation and the consequent related tauopathy in AD.

Amyloid beta-Peptides↗

PubMed2004

The interaction of cannabinoids and opioids on pentylenetetrazole-induced seizure threshold in mice.

Cannabinoid and opioid receptor agonists show functional interactions in a number of their physiological effects. Regarding the seizure-modulating properties of both classes of receptors, the present study examined the possibility of a functional interaction between these receptors. We used acute systemic administration of cannabinoid selective CB(1) receptor agonist (ACPA) and antagonist (AM251) and opioid receptor agonist (morphine) and antagonists (naltrexone and norbinaltorphimine) in a model of clonic seizure induced by pentylenetetrazole (PTZ). Acute administration of ACPA (1.5-2 mg/kg) increased the PTZ-induced seizure threshold. In contrast, AM251 (0.5-2 mg/kg) dose-dependently decreased the seizure threshold. Low dose of AM251 (0.5 mg/kg), which did not alter seizure threshold by itself, reversed the anticonvulsant effect of ACPA (2 mg/kg), showing a CB(1) receptor-mediated mechanism. Naltrexone (1 or 10 mg/kg) but not specific kappa-opioid receptor antagonist norbinaltorphimine (5 mg/kg) completely reversed the anticonvulsant effect of ACPA (2 mg/kg). Moreover, the combination of the lower doses of AM251 (0.5 mg/kg) and naltrexone (0.3 mg/kg) had an additive effect in blocking the anticonvulsant effect of ACPA. In accordance with previous reports, morphine exerted biphasic effects on clonic seizure threshold with anticonvulsant effect at lower (0.5-1 mg/kg) and proconvulsant effect at a higher (30 mg/kg) doses. The pretreatment with AM251 blocked the anticonvulsant effect of morphine at 1 mg/kg, while pretreatment with ACPA (1 mg/kg) potentiated the anticonvulsant effect of morphine at 0.5 mg/kg. The proconvulsant effect of morphine at 30 mg/kg was also inhibited by AM251 (2 mg/kg). A similar interaction between cannabinoids and opioids was also detected on their anticonvulsant effects against the generalized tonic-clonic model of seizure. In conclusion, cannabinoids and opioids show functional interactions on modulation of seizure susceptibility.

Analysis of Variance↗

PubMed2003

Neurophysiology of pruritus: cutaneous elicitation of itch.

Itching is defined as an unpleasant cutaneous sensation leading to the desire to scratch. It serves as a physiological self-protective mechanism as do other cutaneous sensations like pain, touch, vibration, cold, and heat to help defend the skin against harmful external agents. Pruritus can be evoked in the skin directly by mechanical and thermal stimuli or indirectly through chemical mediators. It may also be generated in the central nervous system independently of peripheral stimulation. Single-nerve-fiber recordings have shown that histamine-evoked itch is transmitted by selective slow-conducting subpopulations of unmyelinated C-polymodal neurons. Recent experimental studies using improved methods have demonstrated which of the suspected chemical itch mediators such as histamine, neuropeptides, prostaglandins, serotonin, acetylcholine, or bradykinin act pruritogenically on C-fibers. Moreover, investigations have revealed new receptor systems such as vanilloid, opioid, and cannabinoid receptors on cutaneous sensory nerve fibers that may modulate itch and thereby represent targets for antipruritic therapy. This review focuses on the peripheral generation of itch, including neurotransmitters, neuropeptides, and inflammatory mediators.

Humans↗

PubMed1996

Cannabinoid modulation of rat pup ultrasonic vocalizations.

The present study investigated the effects of the cannabinoid receptor agonist CP 55,940 (1-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) and the cannabinoid receptor antagonist SR 141716A (N-(piperidin-l-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1 H-pyrazole-3-carboxamide hydrochloride) on ultrasonic vocalizations, body temperature and activity in 11-13-day-old rat pups. Testing occurred in a 5-min session 30 min following drug administration. CP 55,940 produced a dose-dependent decrease in ultrasonic vocalizations, with a 1000-micrograms/kg dose causing an almost complete inhibition of calls. Doses of 100 and 1000 micrograms/kg of CP 55,940, but not 10 micrograms/kg, caused significant hypothermia in the pups and the 1000 micrograms/kg dose also inhibited activity. The cannabinoid receptor antagonist SR 141716A (20 mg/kg) reversed the effects of 1000 micrograms/kg CP 55,940 on ultrasonic vocalizations and body temperature, but the benzodiazepine receptor antagonist flumazenil (20 mg/kg), the dopamine D1 receptor antagonist SCH 23390 (0.5 mg/kg) and the opioid receptor antagonist naloxone (1 mg/kg) did not. When administered alone, SR 141716A (20 mg/kg) increased pup ultrasonic vocalizations without affecting body temperature or activity. These results indicate that cannabinoids modulate ultrasonic vocalization production in rat pups in a manner that is independent of hypothermia. The increase in ultrasonic vocalizations produced by SR 141716A is one of the first reported behavioural effects of this drug and suggests that the endogenous cannabinoid ligand anandamide may be involved in the regulation of ultrasonic vocalizations.

Analysis of Variance↗

PubMed2005

Systemic administration of WIN 55,212-2 increases norepinephrine release in the rat frontal cortex.

Cannabinoid agonists modulate a variety of behavioral functions by activating cannabinoid receptors that are widely distributed throughout the central nervous system. In the present study, norepinephrine efflux was assessed in the frontal cortex of rats that received a systemic administration of the cannabinoid agonist, WIN 55,212-2. The synthetic cannabinoid agonist dose-dependently increased the release of norepinephrine in this brain region. Pretreatment with the cannabinoid receptor antagonist, SR 141716A, blocked the increase in norepinephrine release. To identify sites of cellular activation, immunocytochemical detection of c-Fos was combined with detection of the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH), in the brainstem nucleus locus coeruleus (LC), a region that is the sole source of norepinephrine to the frontal cortex. Systemic administration of WIN 55,212-2 significantly increased the number of c-Fos immunoreactive cells within TH-containing neurons in the LC compared to vehicle-treated rats. Pretreatment with SR 141716A inhibited the WIN 55,212-2 induced c-Fos expression, while the antagonist alone did not affect c-Fos expression. Taken together, these data indicate that systemically administered cannabinoid agonists stimulate norepinephrine release in the frontal cortex by activating noradrenergic neurons in the coeruleo-frontal cortex pathway. These effects may partially underlie changes in attention, arousal and anxiety observed following exposure to cannabis-based drugs.

Analysis of Variance↗

PubMed2001

Biological activity of plant extracts: novel analgesic drugs.

The plant-derived secondary metabolites have, over the years, greatly contributed to our current understanding of the important mechanisms related to the process of pain transmission and treatment. Furthermore, they have permitted us to characterise receptor types and identify endogenous ligands involved in the mechanism of nociception. In this review, we discuss the recent advances that have occurred regarding plant-derived substances in the process of development of new analgesic drugs. Plants, such as Papaver somniferum, Cannabis sativa and those of the Capsicum and Salix species, have greatly accounted for the development of clinically relevant drugs which are useful for the management of pain disorders. The recent advances in our understanding of the mechanisms of action of the above plant-derived substances, together with use of molecular biology techniques, have greatly accelerated attempts to identify promising targets for the discovery of new, safe and efficient analgesic drugs. Despite the great progress which has occurred in the elucidation of pain transmission and despite decades of use, leaving aside its known undesirable sides effects, morphine continues to be one of the most used drugs in clinical practice for the treatment of pain disorders. Thus, safer and more efficacious analgesic drugs are urgently needed. A search through the literature reveals that many potentially active antinociceptive plant-derived compounds have been identified. However, studies aiming to investigate their cellular and molecular mechanisms of action and well-controlled clinical trials to prove their efficacy in humans are still lacking. Nevertheless, natural or synthetic substances that bind to vanilloid or cannabinoid receptors, or even those that are capable of modulating the endogenous ligands which bind to these receptors, are expected to soon appear to assist in the treatment of several pain disorders, including those of neuropathic or neurogenic origin.

Journal Article↗

PubMed1996

Biosynthesis of anandamide and related acylethanolamides in mouse J774 macrophages and N18 neuroblastoma cells.

Anandamide (arachidonoylethanolamide, AnNH) has been recently proposed as the endogenous ligand at the brain cannabinoid receptor CB1. Two alternative pathways have been suggested for the biosynthesis of this putative mediator in the central nervous system. Here we present data (1) substantiating further the mechanism by which AnNH is produced by phospholipase D (PLD)-catalysed hydrolysis of N-arachidonoylphosphatidylethanolamine in mouse neuroblastoma N18TG2 cells, and (2) suggesting for the first time that AnNH is biosynthesized via the same mechanism in a non-neuronal cell line, mouse J774 macrophages, together with other acylethanolamides and is possibly involved in the control of the immune/inflammatory response. Lipids from both neuroblastoma cells and J774 macrophages were shown to contain a family of N-acylphosphatidylethanolamines (N-aPEs), including the possible precursor of AnNH, N-arachidonoyl-PE. Treatment with exogenous PLD, but not with exogenous phospholipase A2 and ethanolamine, resulted in the production of a series of acylethanolamides (AEs), including AnNH, from both cell types. The formation of AEs was accompanied by a decrease in the levels of the corresponding N-aPEs. Enzymically active homogenates from either neuroblastoma cells or J774 macrophages were shown to convert synthetic N-[3H]arachidonoyl-PE into [3H]AnNH, thus suggesting that in both cells an enzyme is present which is capable of catalysing the hydrolysis of N-aPE(s) to the corresponding AE(s). Finally, as previously shown in central neurons, on stimulation with ionomycin, J774 macrophages also produced a mixture of AEs including AnNH and palmitoylethanolamide, which has been proposed as the preferential endogenous ligand at the peripheral cannabinoid receptor CB2 and, consequently, as a possible down-modulator of mast cells. On the basis of this as well as previous findings it is now possible to hypothesize for AnNH and palmitoylethanolamide, co-synthesized by macrophages, a role as peripheral mediators with multiple actions on blood cell function.

Animals↗

PubMed2003

Effects of cannabinoids on endogenous K+ and Ca2+ currents in HEK293 cells.

Effects of cannabinoids on endogenous potassium and calcium currents in HEK293 cells were studied using the whole-cell variant of the patch-clamp technique. The cannabinoid agonists WIN 55,212-2, methanandamide, and anandamide (1 microM) decreased the calcium current by 53.1 +/- 2.6, 47.5 +/- 1.2, and 38.8 +/- 3.1%, respectively, after transfection of human CB1 cannabinoid receptor (hCB1) cDNA into HEK293 cells. The delayed rectifier-like current was not changed after application of these agonists, but the inward rectifier was increased by 94.0 +/- 3.6, 83.7 +/- 5.1, and 63.0 +/- 2.5% after application of WIN 55,212-2, methanandamide, and anandamide, respectively. The effects of the cannabinoid antagonists (AM251, AM281, and AM630) on the inward rectifier and calcium currents were the opposite of those seen with cannabinoid agonists; thus, these compounds act as inverse agonists in this preparation. These results suggest that endogenous inward rectifier and calcium currents are modulated by cannabinoids in HEK293 cells, and that some expressed receptors may be constitutively active.

Arachidonic Acids↗

PubMed2005

Unheated Cannabis sativa extracts and its major compound THC-acid have potential immuno-modulating properties not mediated by CB1 and CB2 receptor coupled pathways.

There is a great interest in the pharmacological properties of cannabinoid like compounds that are not linked to the adverse effects of Delta(9)-tetrahydrocannabinol (THC), e.g. psychoactive properties. The present paper describes the potential immuno-modulating activity of unheated Cannabis sativa extracts and its main non-psychoactive constituent Delta(9)-tetrahydrocanabinoid acid (THCa). By heating Cannabis extracts, THCa was shown to be converted into THC. Unheated Cannabis extract and THCa were able to inhibit the tumor necrosis factor alpha (TNF-alpha) levels in culture supernatants from U937 macrophages and peripheral blood macrophages after stimulation with LPS in a dose-dependent manner. This inhibition persisted over a longer period of time, whereas after prolonged exposure time THC and heated Cannabis extract tend to induce the TNF-alpha level. Furthermore we demonstrated that THCa and THC show distinct effects on phosphatidylcholine specific phospholipase C (PC-PLC) activity. Unheated Cannabis extract and THCa inhibit the PC-PLC activity in a dose-dependent manner, while THC induced PC-PLC activity at high concentrations. These results suggest that THCa and THC exert their immuno-modulating effects via different metabolic pathways.

Cannabis↗

PubMed2006

Cannabinoids modulate the P-type high-voltage-activated calcium currents in purkinje neurons.

Endocannabinoids released by postsynaptic cells inhibit neurotransmitter release in many central synapses by activating presynaptic cannabinoid CB1 receptors. In particular, in the cerebellum, endocannabinoids inhibit synaptic transmission at granule cell to Purkinje cell synapses by modulating presynaptic calcium influx via N-, P/Q-, and R-type calcium channels. Using whole cell patch-clamp techniques, we show that in addition to this presynaptic action, both synthetic and endogenous cannabinoids inhibit P-type calcium currents in isolated rat Purkinje neurons independent of CB1 receptor activation. The IC50 for the anandamide (AEA)-induced inhibition of P-current peak amplitude was 1.04 +/- 0.04 microM. In addition, we demonstrate that all the tested cannabinoids in a physiologically relevant range of concentrations strongly accelerate inactivation of P currents. The effects of AEA cannot be attributed to the metabolism of AEA because a nonhydrolyzing analogue of AEA, methanandamide inhibited P-type currents with a similar efficacy. All effects of cannabinoids on P-type Ca2+ currents were insensitive to antagonists of CB1 cannabinoid or vanilloid TRPV1 receptors. In cerebellar slices, WIN 55,212-2 significantly affected spontaneous firing of Purkinje neurons in the presence of CB1 receptor antagonist, in a manner similar to that of a specific P-type channel antagonist, indicating a possible functional implication of the direct effects of cannabinoids on P current. Taken together these findings demonstrate a functionally important direct action of cannabinoids on P-type calcium currents.

Animals↗

PubMedDate not supplied

Inhibitory interaction of cannabinoid CB1 receptor and dopamine D2 receptor agonists on voltage-gated currents of goldfish cones.

Dopamine is a light-adaptive signal that desensitizes the retina, while cannabinoids reportedly increase photosensitivity. The presynaptic membrane of goldfish retinal cones has dopamine D2 receptors and cannabinoid CB1 receptors. This work focused on whether dopamine D2 receptor agonist quinpirole and cannabinoid CB1 receptor agonist WIN 55212-2 (WIN) interacted to modulate voltage-dependent membrane currents of cones. A conventional patch-clamp method was used to record depolarization evoked whole-cell outward currents (Iout) and an inward calcium current (ICa) from the inner segment of cones in goldfish retinal slices. WIN had biphasic actions: low concentrations (<1 microM) increased the currents via Gs, while higher concentrations (>1 microM) decreased the currents via Gi/Go. Neither dopamine nor the D2 agonist quinpirole (1-20 microM) had a significant effect on either Iout or ICa. Quinpirole at 50 microM had a mild suppressive (approximately 20%) effect on Iout. However, quinpirole (<10 microM) completely blocked the enhancement of both currents seen with 0.7 microM WIN. The effect of quinpirole was blocked by sulpiride and by pertussis toxin, indicating that quinpirole was acting via a D2 receptor-Gi/o coupled mechanism. The suppressive action of 50 microM quinpirole (approximately 20%) was not additive with the suppressive effect of 3 microM WIN (approximately 40%). D2 agonists via Gi/o oppose the action of low concentrations of CB1 agonists acting via Gs to modulate cone membrane currents, suggesting a role in shaping the cone light response and/or sensitivity to changes in ambient light conditions. The nonadditive effect of high concentrations of WIN and quinpirole suggests that both decrease membrane currents via the same transduction pathway, Gi/Go protein kinase A (PKA).

Animals↗

PubMed1999

A light and electron microscopic study of the CB1 cannabinoid receptor in primate brain.

The immunohistochemical distribution and subcellular localization of the cannabinoid CB1 receptor was determined in the adult monkey using a polyclonal antiserum raised against the amino terminus of the rat CB1 receptor. At the level of light microscopy, our results generally parallel earlier studies investigating CB1 distribution in rodent brain with a few differences. In particular, high levels of receptor were found in the cortex, hippocampus, amygdala, cerebellum. However significant differences were also noted. The most striking differences were high levels of CB1 receptor in the monkey substantia nigra pars compacta, cerebellar Purkinje cells, and the principal cells of the hippocampus, while few receptors were found in the globus pallidus or substantia nigra pars reticulata. In contrast, in a previous study investigating the rat, using the same antibody, the opposite staining pattern was observed. At the electron microscopic level CB1 receptor was restricted to neurons. Here it was found both pre- and postsynaptically, particularly on dendritic spines and axon terminals. The CB1 receptor is widely distributed in higher brain regions in the monkey. While its distribution is similar to that in the rat, there are major differences, some of which may be significant when extrapolating the behavioral effects of cannabinoids observed in rodents to primates (e.g., humans). The ultrastructural localization of the CB1 receptor suggests that it modulates neuronal excitability by both pre- and postsynaptic mechanisms.

Animals↗

PubMed2004

Differential effects of THC- or CBD-rich cannabis extracts on working memory in rats.

Cannabinoid receptors in the brain (CB(1)) take part in modulation of learning, and are particularly important for working and short-term memory. Here, we employed a delayed-matching-to-place (DMTP) task in the open-field water maze and examined the effects of cannabis plant extracts rich in either Delta(9)-tetrahydrocannabinol (Delta(9)-THC), or rich in cannabidiol (CBD), on spatial working and short-term memory formation in rats. Delta(9)-THC-rich extracts impaired performance in the memory trial (trial 2) of the DMTP task in a dose-dependent but delay-independent manner. Deficits appeared at doses of 2 or 5 mg/kg (i.p.) at both 30 s and 4 h delays and were similar in severity compared with synthetic Delta(9)-THC. Despite considerable amounts of Delta(9)-THC present, CBD-rich extracts had no effect on spatial working/short-term memory, even at doses of up to 50 mg/kg. When given concomitantly, CBD-rich extracts did not reverse memory deficits of the additional Delta(9)-THC-rich extract. CBD-rich extracts also did not alter Delta(9)-THC-rich extract-induced catalepsy as revealed by the bar test. It appears that spatial working/short-term memory is not sensitive to CBD-rich extracts and that potentiation and antagonism of Delta(9)-THC-induced spatial memory deficits is dependent on the ratio between CBD and Delta(9)-THC.

Animals↗

PubMed1997

Anandamide suppresses nitric oxide and TNF-alpha responses to Theiler's virus or endotoxin in astrocytes.

Astrocytes are an important cell population in the CNS, involved in cytokine homeostasis and participating in a variety of important physiological and pathological processes. In the present study we showed that primary cultures of neonatal mouse cortical astrocytes stimulated with lipopolysaccharide (Balb/c mice strain, LPS: 1 microgram/ml, 18 h) or Theiler's virus, TMEV (SJL/J mice strain, TMEV: 10(5) PFU/well, 24 h) released an increased amount of nitrites (NO2-) and tumour necrosis factor-alpha (TNF-alpha) into the culture medium. Exogenous cannabinoids are known to modulate the function of immune cells. Anandamide, an endogenous ligand for the cannabinoid receptor, blocked the release of NO2- and TNF-alpha induced by LPS in a dose-dependent manner. In TMEV-stimulated astrocytes anandamide also suppressed, in a dose-related manner, the stimulatory effects of TMEV on both NO2- and TNF-alpha. It is suggested that anandamide exerts an immunoregulatory role in the CNS. These results could have important implications in the modulation of immunological and inflammatory processes by cannabinoid agents.

Animals↗

PubMed2004

Receptor-independent depression of DA and 5-HT uptake by cannabinoids in rat neocortex--involvement of Na(+)/K(+)-ATPase.

There is evidence that cannabinoids modulate the reuptake of some neurotransmitters in the central nervous system. In this study, we investigated the effects of the synthetic cannabinoid receptor agonist WIN55212-2, the endocannabinoid anandamide and the chemically related arachidonic acid on serotonin (5-HT) and dopamine (DA) uptake into rat neocortical synaptosomes. At micromolar concentrations, anandamide and arachidonic acid produced steep inhibition curves with Hill coefficients above unity. WIN55212-2 inhibited both DA and 5-HT uptake with Hill coefficients near unity, also within the micromolar range. The effect of WIN55212-2 was not mediated by cannabinoid receptors, since the CB1 receptor antagonist AM251 failed to diminish uptake inhibition by WIN55212-2 and since the Ki estimates of WIN55212-2 were outside the range of the dissociation constants of WIN55212-2 at both CB1 and CB2 receptors. A 100-fold higher concentration of DA, respectively 5-HT, did not induce a shift to the right of the WIN55212-2 concentration-inhibition curves, suggesting a carrier-independent mechanism. The Na(+)/K(+)-ATPase inhibitor ouabain concentration dependently inhibited 5-HT uptake. Possible drug effects on commercial Na(+)/K(+)-ATPase and synaptosomal ATP consumption were investigated using an ATP bioluminescence assay. Ouabain inhibited both commercial and synaptosomal Na(+)/K(+)-ATPase. WIN55212-2 had no effect on commercial Na(+)/K(+)-ATPase, but inhibited synaptosomal ATP consumption. Anandamide produced a sharp decrease in the activity of commercial Na(+)/K(+)-ATPase and on synaptosomal ATP consumption. Presence of ouabain significantly reduced the inhibitory effect of anandamide on synaptosomal ATP consumption, whereas the effect of WIN55212-2 remained unchanged. Our results show that cannabinoids and arachidonic acid inhibit DA and 5-HT uptake into rat neocortical synaptosomes. This effect is neither cannabinoid receptor-mediated nor due to competitive inhibition of membrane transporters, but is partly effected by a decreased Na(+)/K(+)-ATPase activity.

Adenosine Triphosphate↗

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↗