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B R Martin

Publications and source records attributed to B R Martin.

At least 73 records · Page 4Linked to original sources
PubMed1999

Pharmacological characterization of nicotine's interaction with cocaine and cocaine analogs.

Cocaine and a number of 3beta-phenyltropane cocaine analogs were investigated for their potential to block various pharmacological effects of nicotine in animals. They blocked the antinociceptive effect of nicotine in the tail-flick test after systemic administration in a dose-dependent manner. Similarly, cocaine was also able to block nicotine-induced motor impairment in mice. Furthermore, cocaine blocked nicotine-induced seizures at a lower potency than for antinociception, but failed to block nicotine's effect on body temperature and drug discrimination. The antagonistic potencies of the 3beta-phenyltropane cocaine analogs were not correlated with their affinity for monoamines transporters. Additionally, bupropion, nomifensin, GBR 12909, and nisoxetine, but not methylphenidate and fluoxetine, blocked nicotine-induced antinociception; however, their antagonistic potencies were unrelated to their affinities for the transporters. Taken together, these results suggest that the mechanism of cocaine's antagonistic activity is not related to its binding and uptake of inhibition on monoamine neurotransporters. The failure of lidocaine and procaine to antagonize nicotine's effects in the tail-flick assay rules out local anesthetic effects. In addition, cocaine blocked differentially the response of nicotine in the oocyte receptor expression system for the alpha4beta2 and alpha3beta2 subtypes in a dose-dependent manner. Our results suggest that cocaine is a noncompetitive nicotinic antagonist with some selectivity for neuronal nicotinic receptor subtypes. Our studies also demonstrate that 3beta-phenyltropane analogs constitute a new class of nicotinic antagonists. Elucidation of the mechanism of action of this new class of antagonists may provide an explanation for the effectiveness of agents such as bupropion for the treatment of smoking cessation.

Animals↗
PubMed1999

Manipulation of the tetrahydrocannabinol side chain delineates agonists, partial agonists, and antagonists.

Structure-activity relation studies have established that the alkyl side chain in tetrahydrocannabinol (THC) plays a crucial role in the activation of the cannabinoid receptor. Unfortunately, the flexible nature of this side chain has hampered efforts to elucidate the precise nature of the interaction of THC with its receptors. Therefore, a series of analogs with structurally restrained side chains of varying length was synthesized and evaluated for pharmacological potency in mice and for receptor affinity. The introduction of cis double bonds inserted rigid angles, whereas triple bonds developed regions of planarity. Receptor affinity for the acetylenic and saturated side chains were the same, whereas double bond substitution increased affinity 10-fold. Moreover, the relationship between receptor affinity and potency was 10-fold less than that of Delta(8)-THC in the case of some acetylenic derivatives, whereas changing the triple bond to a double bond restored the potency/affinity ratio. Additionally, an acetylene at C2-C3 in the octyl and nonyl side chains favored antinociception by as much as 70-fold. Surprisingly, several high-affinity acetylenic derivatives, especially those with cyano substitutions at the terminus of the side chain, were partial agonists or were inactive. Some of these low-efficacy, high-affinity ligands elicited antagonistic activity. The finding that manipulations of the side chain produces high- affinity ligands with either antagonist, partial agonist, or full agonist effects reveals a critical structural feature for receptor activation.

Animals↗
PubMed1999

Cannabimimetic fatty acid derivatives: the anandamide family and other endocannabinoids.

In agreement with the highly lipophilic nature of (-)-delta9-tetrahydrocannabinol, all the endogenous ligands of cannabinoid receptors identified so far are derivatives of long chain fatty acids. N- Arachidonoylethanolamine (anandamide) and some of its polyunsaturated congeners have been found in mammalian brain and shown to activate the CB1 and, with a lower efficacy, CB2 cannabinoid receptor subtypes. More recently, 2-arachidonoylglycerol (2-AG), a widespread intermediate in the metabolism of phosphoglycerides, diacylglycerols and triglycerides, was also found to activate the cannabinoid receptors. The capability of palmitoylethanolamide, an anti-inflammatory metabolite, to activate CB2-like receptors is still being debated. Here we review: 1) the metabolic pathways suggested so far to underlie the biosynthesis and inactivation of anandamide and 2-AG, and 2) the current knowledge of the chemical bases for the interactions of anandamide and 2-AG with proteins of the endogenous cannabinoid system characterized so far, i.e. the CB1 and CB2 receptor subtypes, the membrane anandamide carrier , which facilitates anandamide diffusion into cells, and the enzyme fatty acid amide hydrolase , which catalyzes anandamide and, to a certain extent, 2-AG hydrolysis in vivo.

Animals↗
PubMed1999

Antinociceptive and pharmacological effects of metanicotine, a selective nicotinic agonist.

Metanicotine [N-methyl-4-(3-pyridinyl)-3-butene-1-amine], a novel neuronal nicotinic agonist, was found to bind with high affinity (K(i) = 24 nM) to rat brain [(3)H]nicotine binding sites and it generalized to nicotine in a dose-dependent manner in the drug discrimination procedure. Metanicotine produced significant antinociceptive effects in mice and rats subjected to either acute thermal (tail-flick), mechanical (paw-pressure), chemical (para-phenylquinone), persistent (Formalin), and chronic (arthritis) pain stimuli. Metanicotine was about 5-fold less potent than nicotine in the tail-flick test after s.c administration, but slightly more potent after central administration. Its duration of action was longer than that of nicotine. Nicotinic antagonists, mecamylamine and dihydro-beta-erythroidine, blocked metanicotine-induced antinociception in the different pain models. However, the antinociceptive effect was not affected by pretreatment with either naloxone or by atropine, confirming that metanicotine exerts its antinociceptive effect via nicotinic rather than either opioid or muscarinic mechanisms. In contrast to nicotine, antinociceptive effects of metanicotine were observed at doses that had virtually no effect on spontaneous activity and body temperature in mice. These data indicate that metanicotine is a centrally acting neuronal nicotinic agonist with preferential antinociceptive effects in animals. Thus, metanicotine and related nicotinic agonists may have great potential for development as a new class of analgesics.

Analgesics↗
PubMed1999

Pharmacological characterization of nicotine-induced seizures in mice.

Pharmacological mechanisms involved in nicotine-induced seizures were investigated in mice by testing the ability of several nicotinic agonists in producing seizures after peripheral administration. In addition, nicotinic antagonists such as hexamethonium, mecamylamine, dihydro-beta-erythroidine, and methyllycaconitine citrate (MLA) were used in combination with nicotine. We also examined the involvement of calcium channels, N-methyl-D-aspartate receptors, and nitric oxide formation in nicotine-induced seizures. Our results showed that the peripheral administration of nicotine produced seizures in a stereospecific and mecamylamine-sensitive manner. Nicotine-induced seizures are centrally mediated and involve the activation of alpha7 along with other nicotinic receptor subunits. Indeed, MLA, an alpha7-antagonist, blocked the effects of nicotine after peripheral and central administration. The extent of alpha4beta2-receptor subtype involvement in nicotine-induced seizures was difficult to assess. On one hand, we observed that dihydro-beta-erythroidine (a competitive antagonist) failed to block the effects of nicotine. In addition, a poor correlation was found between binding affinity for (3)H-nicotine-labeled sites (predominantly alpha4beta2) and seizures potency for several nicotinic agonists. On the other hand, mecamylamine, a noncompetitive antagonist, blocked nicotine-induced seizures more potently than MLA. Furthermore, its potency in blocking seizures was in the same general dose range of other nicotinic effects that are not alpha7 mediated. These results suggest that this receptor subtype does not play a major role in nicotine-induced seizures. Our findings also suggest that nicotine enhances the release of glutamate either directly or indirectly (membrane depolarization that opens L-type calcium channels). Glutamate release in turn stimulates N-methyl-D-aspartate receptors, thus triggering the cascade of events leading to nitric oxide formation and possibly seizure production.

Animals↗
PubMed1998

Potent cyano and carboxamido side-chain analogues of 1', 1'-dimethyl-delta8-tetrahydrocannabinol.

The synthesis and pharmacological profile of several cyano (1a-e) and carboxamido (2a-h) side-chain-substituted analogues of 1', 1'-dimethyl-Delta8-THC are described. Commercially available cyano compound 3 was transformed to the resorcinol 6 in a three-step sequence. Condensation of 6 with p-menth-2-ene-1,8-diol formed the THC 7a which, with sodium cyanide/DMSO, gave 1b. Protection of the phenol in 7a as the MOM derivative provided the common intermediate 8 for the synthesis of 1a,c,e. Compound 1d was also synthesized from 7a via the aldehyde 9a. Base hydrolysis of 1b gave the acid 10 which, via its acid chloride and subsequent treatment with the appropriate amine, formed the target compounds 2a-h. The pharmacological profile indicated that the cyano analogues 1a-e had very high CB1 binding affinity (0.36-13 nM) and high in vivo potency as agonists. Two analogues (1a,b) had extremely high potency in the mouse tetrad tests. The dimethylcarboxamido analogue 2a showed a similar profile to 1a,b. The high potency was also retained in analogue 2c. In contrast the sulfonamide analogue 2d was unique as it had greater affinity than Delta9-THC, yet it was practically devoid of agonist effects. This study suggests that the incorporation of a cyano or an amide substituent in the side chain of Delta8-THC-DMH can enhance potency and can also lead to compounds with a unique profile which have high binding affinity and are practically devoid of agonist effects.

Animals↗
PubMed1998

Effects of SR 141716A after acute or chronic cannabinoid administration in dogs.

The effects of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamide HCl (SR 141716A), a specific cannabinoid receptor antagonist, were assessed in the dog static ataxia test after either acute treatment with two cannabinoid receptor agonists, delta9-tetrahydrocannabinol and arachidonylethanolamide (anandamide), or chronic treatment with delta9-tetrahydrocannabinol. As previously reported, acute intravenous (i.v.) injected delta9-tetrahydrocannabinol produced dose-dependent cannabinoid effects, including marked static ataxia, prancing, loss of muscle tone, and incoordination. The behavioral profile of anandamide was distinctly different in that it produced a loss of muscle tone and considerable sedation with little static ataxia, prancing, or incoordination. Despite these qualitative differences between the two agonists, SR 141716A blocked the acute behavioral effects of both drugs indicating a cannabinoid receptor mechanism of action. Interestingly, SR 141716A was able to precipitate a withdrawal syndrome in delta9-tetrahydrocannabinol-tolerant dogs, but failed to produce any observable effects in dogs receiving chronic vehicle injections. Acute toxicity caused by anandamide, which was not blocked by SR 141716A, precluded conducting dependence studies with this drug. The delta9-tetrahydrocannabinol precipitated withdrawal syndrome included diarrhea, vomiting, excessive salivation, decreases in social behavior, and increases in restless behavior and trembling. This is the first demonstration of a precipitated withdrawal syndrome in a non-rodent species.

Animals↗
PubMed1998

Evaluation of cannabimimetic effects of structural analogs of anandamide in rats.

Arachidonylethanolamide (anandamide), an endogenous ligand for the cannabinoid receptor, binds competitively to brain cannabinoid receptors and shares many, but not all, of the in vivo effects of delta9-tetrahydrocannabinol. In this study, the cannabinoid effects of anandamide analogs in which the anandamide molecule was altered were assessed in a drug discrimination model. Structural manipulations of the anandamide molecule included saturation of the arachidonyl moiety with fluorination (O-586), substitution for either the ethanolamide moiety (O-612 and O-595) or C2' hydroxyl (O-585), and addition of a methyl group at various positions (O-610, O-680, and O-689). Despite the low binding affinities of the non-methylated compounds (Ki values > 2000 nM), all of the analogs had previously shown cannabinoid activity in mice. In the present study, these analogs were tested in a more pharmacologically specific delta9-tetrahydrocannabinol discrimination procedure in rats. This animal model is predictive of the subjective effects of marijuana intoxication in humans. Whereas delta9-tetrahydrocannabinol and an aminoakylindole fully substituted for the training dose of 3 mg/kg delta9-tetrahydrocannabinol, anandamide and its non-methylated analogs were not cannabimimetic in this procedure. Methylation appeared to increase binding affinity (Ki values < 150 nM) and efficacy; however, the greatest substitution produced by the methylated analogs occurred only at doses that decreased overall rates of responding, suggesting that these analogs are not fully delta9-tetrahydrocannabinol-like. The rapid metabolism of anandamide and some of its analogs undoubtedly contribute to the differences between the pharmacological profiles of the anandamides and classical cannabinoids. These results support the prediction that the subjective effects of anandamide analogs that have been developed thus far would not be cannabimimetic except at high doses.

Animals↗
PubMed1998

Cannabinoid transmission and pain perception.

The use of cannabis for the management of a wide range of painful disorders has been well documented in case reports throughout history. However, clinical evaluations of cannabis and its psychoactive constituent THC have not led to a consensus regarding their analgesic effectiveness. On the other hand, THC and its synthetic derivatives have been shown to be effective in most animal models of pain. These antinociceptive effects are mediated through cannabinoid receptors in the brain that in turn appear to interact with noradrenergic and kappa opioid systems in the spinal cord to modulate the perception of painful stimuli. The endogenous ligand, anandamide, is also an effective antinociceptive agent. The extent to which the endogenous cannabinoid system is involved in the modulation of pain is currently unknown.

Analgesics↗
PubMed1998

Synthesis and pharmacology of the isomeric methylheptyl-delta8-tetrahydrocannabinols.

The synthesis of the 3-heptyl, and the eleven isomeric 3-methylheptyl-delta8-tetrahydrocannabinols (3-7, R and S methyl epimers, and 8) has been carried out. The synthetic approach entailed the synthesis of substituted resorcinols, which were subjected to acid catalyzed condensation with trans-para-menthadienol to provide the delta8-THC analogue. The 1'-, 2'- and 3'-methylheptyl analogues (3-5) are considerably more potent than delta8-THC. The 4'-, 5'- and 6'-methylheptyl isomers (6-8) are approximately equal in potency to delta8-THC.

Animals↗
PubMed1998

Antinociceptive responses to nicotinic acetylcholine receptor ligands after systemic and intrathecal administration in mice.

The objective of this study was to determine which nicotinic receptor subtypes are involved in antinociception and their site of action. For that, the antinociceptive effects of several nicotinic receptor ligands were evaluated in the tail-flick test both after s.c. and intrathecal (i.t.) administration. Nicotine and other nicotine agonists increased tail-flick latencies in a dose-dependent manner after both routes of administration. Epibatidine enantiomers were the most potent agonists examined. Cytisine, a potent nicotinic ligand, failed to elicit antinociception when injected either i.t. or s.c. Despite some similarities in the effects of nicotinic agonists after i.t. and s.c. injections, their rank-order potency was different. In contrast to the s.c. results, the stereoselectivity of nicotine's effect after i.t. administration was minimal. When various nicotinic antagonists were compared after i.t. and s.c. administration, the results showed that mecamylamine and dihydro-beta-erythroidine differ in potency and their degree of antagonism of some of the nicotinic agonists given i.t. These data suggest that different subtypes of nicotinic receptors may exist in the spinal cord. A good correlation was found between binding affinity to [3H]-nicotine binding sites and analgesic potency after i.t. (r = 0.82), suggesting the involvement of alpha 4 beta 2 receptor subunits. In contrast, studies with MLA and alpha-BGTX suggested a minimal role for alpha-BGTX-sensitive receptors in the antinociceptive effect of nicotinic agonists.

Alkaloids↗
PubMed1998

Assessment of anandamide interaction with the cannabinoid brain receptor: SR 141716A antagonism studies in mice and autoradiographic analysis of receptor binding in rat brain.

Anandamide is the newly discovered endogenous cannabinoid ligand that binds to brain cannabinoid receptors and shares most, but not all, of the pharmacological properties of delta 9-THC. Therefore, this study was undertaken to determine whether its interaction with the CB1 receptor in brain was identical to that of delta 9-THC. Anandamide depressed spontaneous activity and produced hypothermia, antinociception and immobility in mice after i.v. administration. However, none of these effects was blocked by pretreatment with the selective CB1 antagonist, SR 141716A. However, the metabolically stable analog 2-methyl-2'-fluoroethylanandamide produced reductions in motor activity and antinociception in mice, effects that were blocked by the antagonist. To determine whether anandamide's receptor binding mimicked that of other cannabinoids, an autoradiographic comparison of anandamide, SR 141716A and CP 55,940 competition for [3H]CP55,940 binding was conducted throughout rat brain. The receptor affinities for all three compounds did not change according to brain area. As expected, Bmax values differed dramatically among differ brain areas. However, the Bmax values for each brain area were similar regardless of the compound used for displacement. These data suggest that anandamide, SR 141716A and CP 55,940 compete for the same cannabinoid receptor throughout brain despite SR 141716A's failure to block anandamide's pharmacological effects. Although there is no question that anandamide binds to the cannabinoid receptor, failure of SR 141716A to block its pharmacological effects in mice poses a dilemma. The results presented herein raise the possibility that anandamide may not be producing all of its effects by a direct interaction with the CB1 receptor.

Animals↗
PubMed1998

Evaluation of cannabinoid receptor agonists and antagonists using the guanosine-5'-O-(3-[35S]thio)-triphosphate binding assay in rat cerebellar membranes.

Cannabinoid receptors are members of the superfamily of G protein-coupled receptors. Their activation has previously been shown to stimulate guanosine 5'-O-(3-[35S]thio)-triphosphate ([35S]GTP gamma S) binding in a range of brain regions using both membrane preparations and autoradiography. This study evaluates the activities of structurally diverse cannabinoid receptor ligands in the GTP gamma S binding assay, comparing the relationship between receptor binding and activation and also examining efficacy differences between compounds. Using rat cerebellar membrane preparations, the effects of GDP concentration on GTP gamma S binding and the activities of a range of cannabinoid receptor ligands, including the CB1 selective antagonist SR141716A, were investigated. GDP concentration was found to have differing effects on cannabinoid-stimulated [35S]GTP gamma S binding depending on the nature of the agonist used. The stimulation produced by high efficacy compounds, such as CP 55,940 and WIN 55212-2, was increased by raising the GDP concentration, but that of a low efficacy agonist, (-)-delta-tetrahydrocannabinol, was decreased. Of the cannabinoid compounds tested, a wide range of potencies (EC50) and levels of maximal stimulation (Emax) were observed. These ranged from CP 55,244 (Emax of 165, 148-183%, and an EC50 of 0.47, 0.22-0.96, nM) through (-)-delta-tetrahydrocannabinol, cannabinol and anandamide, which produced no concentration-dependent stimulation of [35S]GTP gamma S binding under the same conditions. SR141716A competitively antagonized all the agonists against which it was tested, providing equilibrium dissociation constants (Kd values) in the sub-nanomolar range (0.06-0.40 nM), implicating a CB1 receptor mediated response. These results provide a more detailed characterization of the cannabinoid-stimulated [35S]GTP gamma S binding assay than has previously been reported.

Animals↗
PubMed1998

Structure-activity relationships of indole- and pyrrole-derived cannabinoids.

Early molecular modeling studies with Delta9-tetrahydrocannabinol (Delta9-THC) reported that three discrete regions which interact with brain cannabinoid (CB1) receptors corresponded to the C-9 position of the cyclohexene ring, the phenolic hydroxyl and the carbon side chain at the C3 position. Although the location of these attachment points for aminoalkylindoles is less clear, the naphthalene ring, the carbonyl group and the morpholinoethyl group have been suggested as probable sites. In this study, a series of indole- and pyrrole-derived cannabinoids was developed, in which the morpholinoethyl group was replaced with another cyclic structure or with a carbon chain that more directly corresponded to the side chain of Delta9-THC and were tested for CB1 binding affinity and in a battery of in vivo tests, including hypomobility, antinociception, hypothermia and catalepsy in mice and discriminative stimulus effects in rats. Receptor affinity and potency of these novel cannabinoids were related to the length of the carbon chain. Short side chains resulted in inactive compounds, whereas chains with 4 to 6 carbons produced optimal in vitro and in vivo activity. Pyrrole-derived cannabinoids were consistently less potent than were the corresponding indole derivatives and showed pronounced separation of activity, in that potencies for hypomobility and antinociception were severalfold higher than potencies for hypothermia and ring immobility. These results suggest that, whereas the site of the morpholinoethyl group in these cannabinoids seems crucial for attachment to CB1 receptors, the exact structural constraints on this part of the molecule are not as strict as previously thought.

Animals↗
PubMed1998

CB1 receptor antagonist precipitates withdrawal in mice exposed to Delta9-tetrahydrocannabinol.

Although tolerance to cannabinoids has been well established, the question of cannabinoid dependence had been very controversial until the discovery of a cannabinoid antagonist, SR141716A. The objective of this study was to develop and characterize a mouse model of precipitated withdrawal indicative of cannabinoid dependence. Using a dosing regimen known to produce pharmacological and behavioral tolerance, mice were treated with Delta9-tetrahydrocannabinol (Delta9-THC) twice a day for 1 wk. SR141716A administration after the last Delta9-THC injection promptly precipitated a profound withdrawal syndrome. Typical withdrawal behavior was an increase in paw tremors and head shakes that was accompanied with a decrease in normal behavior such as grooming and scratching. Of the three Delta9-THC regimens tested, daily Delta9-THC injections of 10 and 30 mg/kg produced the greatest number of paw tremors and head shakes and the least number of grooms after challenge with SR141716A. Precipitated withdrawal was apparent after 2, 3, 7 and 14 days of treatment based on an increase in paw tremors in Delta9-THC-treated mice as compared with vehicle-treated mice. These findings are consistent with SR141716A-precipitated withdrawal in rats. Moreover, these results suggest that mice are a viable model for investigating dependence to cannabinoids.

Analysis of Variance↗
PubMed1998

Anandamide, an endogenous cannabinoid, has a very low physical dependence potential.

Using N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide. HCl (SR 141716A), a cannabinoid antagonist, several investigators (deFonseca et al., 1997; Aceto et al., 1995, 1996; Tsou et al., 1995) demonstrated physical dependence on THC [Delta9-tetrahydrocannabinol]. This demonstration prompted us to determine whether anandamide, an endogenous cannabinoid agonist, would also produce physical dependence. A low-dose regimen (10, 20, 40 and 40) or a high-dose regimen (25, 50, 100 and 100) expressed as mg/kg/24 hr was infused i.p. on a continuous basis, from days 1 through 4, respectively. During the infusion, especially at the high-dose regimen, the rats became immobile and developed eyelid ptosis. Abrupt discontinuation of anandamide did not elicit rebound behavioral activity. Neither arachidonic acid, a precursor and metabolite of anandamide (50, 100, 200 and 200 mg/kg/24 hr on days 1 through 4, respectively), nor 2-Me-F-AN [2-methylarachidonyl-(2'-fluoroethyl)-amide], a metabolically stable analog of anandamide (5, 10, 20 and 20 mg/kg/24 hr for 4 days, respectively), had remarkable effects. Notably, groups pretreated with anandamide or 2-Me-F-AN and challenged with SR 141716A did not show significantly elevated behavioral scores when compared with SR 141716A controls. On the other hand, nearly all groups receiving SR 141716A showed significant activation of these behaviors compared with vehicle controls, which suggests that this cannabinoid antagonist itself was activating behavior. We concluded that anandamide has little if any capacity for physical dependence. The finding that SR 141716A activated behavior supports the hypothesis that the cannabimimetic system exerts a depressant effect in the CNS.

Animals↗
PubMed1997

Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock.

Anandamide, an endogenous cannabinoid ligand, binds to CB1 cannabinoid receptors in the brain and mimics the neurobehavioural actions of marijuana. Cannabinoids and anandamide also elicit hypotension mediated by peripheral CB1 receptors. Here we report that a selective CB1 receptor antagonist, SR141716A, elicits an increase in blood pressure in rats subjected to haemorrhagic shock, whereas similar treatment of normotensive rats or intracerebroventricular administration of the antagonist during shock do not affect blood pressure. Blood from haemorrhaged rats causes hypotension in normal rats, which can be prevented by SR141716A but not by inhibition of nitric oxide synthase in the recipient. Macrophages and platelets from haemorrhaged rats elicit CB1 receptor-mediated hypotension in normotensive recipients, and incorporate arachidonic acid or ethanolamine into a product that co-elutes with anandamide on reverse-phase high-performance liquid chromatography. Also, macrophages from control rats stimulated with ionomycin or bacterial phospholipase D produce anandamide, as identified by gas chromatography and mass spectrometry. These findings indicate that activation of peripheral CB1 cannabinoid receptors contributes to haemorrhagic hypotension, and anandamide produced by macrophages may be a mediator of this effect.

Animals↗