THC and anandamide

Rodriguez 1998). THC- and anandamide-induced analgesia also have different durations (90 min and 15 min, respectively) (Smith et al. 1998). 

The presence of cannabinoid receptors in the immune system has led to consideration of the effects of cannabis on its function. Cannabinoid receptors have been found in spleen cells (Kaminski et al. 1992). Activation of these receptors would inhibit their function in the immune response. Similar suppressant effects occur on lymphocytes (Diaz et al. 1993). THC and anandamide inhibit macrophage-mediated tumor necrosis (Cabral et al. 1995). Despite these effects, their functional significance remains to be determined. These effects are most likely subtle. 

Cannabis, or marijuana, has been used for centuries for both symptomatic and prophylactic treatment of migraine. It was highly esteemed as a headache remedy by the most prominent physicians of the age between 1874 and 1942, remaining part of the Western pharmacopoeia for this indication even into the mid-20th century. Current ethnobotanical and anecdotal references continue to refer to its efficacy for this malady, and biochemical studies of THC and anandamide have provided a scientific basis for such treatment (Russo, 1998). 

Structurally there is little in common between A9-THC and anandamide. The cannabinoids are terpenophenols, while the anandamides are fatty acid derivatives. Yet, pharmacologically they have much in common. Both A9-THC and anandamide were shown to cause a typical tetrad of behavioural actions hypothermia, hypomotility, antinociception and catalepsy. In most behavioural tests, anandamide is somewhat less potent than d9-THC [35, 36]. Repeated injections of anandamide (i.p.) produced tolerance to a challenge with THC or anandamide. This tolerance however was less persistent than that commonly seen with THC, lasting for only one week [37],... 

Williams CM, Kirkham TC (2002a) Observational analysis of feeding inducedby Delta9-THC and anandamide. Physiol Behav 76 241-250... 

Berdyshev et al. (1997) examined the effects of anandamide, palmitoylethanolamide and THC on the production of TNF-a, IL-4, IL-6, IL-8, IL-10, IFN-y, p55, and p75 TNF-a soluble receptors expressed by stimulated human peripheral blood mononuclear cells as well as [ H]-arachidonic acid release by non-stimulated and N-formyl-Met-Leu-Phe (fMLP)-stimulalcd human monocytes. Anandamide diminished IL-6 and IL-8 production at low nanomolar concentrations and inhibited the production of TNF-a, IFN-y, IL-4, and p75 TNF-a soluble receptors at higher concentrations (i.e., micromolar levels). Palmitoylethanolamide inhibited IL-4, IL-6, and IL-8 synthesis and the production of p75 TNF-a soluble receptors at concentrations similar to those of anandamide but did not affect TNF-a and IFN-y production. Neither anandamide nor palmitoylethanolamide influenced IL-10 synthesis. THC, on the other hand, exerted a biphasic effect on pro-inflammatory cytokine production. TNF-a, IL-6, and IL-8 synthesis was inhibited maximally by 3 nM THC but stimulated by 3 pM THC. A similar effect was observed for IL-8 and IFN-y. The level of IL-4, IL-10, and p75 TNF-a soluble receptors was diminished by 3 pM THC. [ H]-Arachidonate release was stimulated only by high THC and anandamide concentrations. Based on these observations, the investigators suggested that the inhibitory properties of anandamide, palmitoylethanolamide, and THC are determined by the activation of peripheral-type cannabinoid receptors (i.e., CB2) and that various endogenous fatty acid ethanolamides also participate in the regulation of the immune response. 

Anandamide is proposed as an endogenous cannabinoid that has been shown to mimic the effects of tetrahydrocannabinol in both in vivo and in vitro systems. Thus, THC and anandamide have common pharmacological properties despite their different structures. The former is a rigid compound whereas the latter is flexible. 

Scorticati et al., 2003, 2004), and increases in adreno-corticotropin hormone (ACTH) and corticosterone release in rats (Weidenfeld et al., 1994 Manzanares et al., 1999). Cannabinoids such as THC and anandamide bind to dense populations of caimabinoid CBi receptors in the brain and, notably, the hypothalamus (Herkenham et al., 1991). Autoradiography studies have demonstrated the presence of CBj receptors in several hypothalamic nuclei involved in neuroendocrine modulation, including the medial preoptic area and the paraventricular nuclei (PVN), predominant sites of GnRH and CRH neuronal cell bodies, respectively (Femandez-Ruiz et al., 1997). 

THC was first isolated from hashish in 1964 by Raphael Mechoulam (1930-) and Yehiel Gaoni at the Weizmann Institute. Mechoulam had obtained 5 kg hashish from Israeli police officials and the earliest scientific work on THC and cannabinoids used this source. In the early 1990s, the specific brain receptors affected by THC were identified. These receptors are activated by a cannabinoid neurotransmitter called arachidonylethanolamide, known as anandamide. Anandamide was named by Mechoulam using ananda, which is the Sanskrit word for ecstasy. Anandamide is thought to be associated with memory, pain, depression, and appetite. THC is able to attach to and activate anandamide receptors. These receptors are actually called THC receptors rather than anandamide receptors because researchers discovered that THC attaches to these receptors before anandamide was discovered. The areas of the brain with the most THC receptors are the cerebellum, the cerebral cortex, and the limbic system. This is why marijuana affects thinking, memory, sensory perception, and coordination. 

Figure 19.1. Chemical structure of main active ingredient of Cannabis sativa, A9-tetrahydrocannabinol (THC) and the naturally occurring ligand for cannabinoid receptors anandamide (arachidonyl ethanolamide).

Lichtman and Martin have shown that cannabinoid-induced antinociception has both spinal and supraspinal components [152]. A spinal a2-noradre-nergic mechanism is involved in cannabinoid antinociception as yohimbine and/or methysergide altered z)9-THC induced antinociceptive effects in rats [153]. A supraspinal mechanism is also involved as cannabinoid analgesia can be produced in spinally transected rats [152], Both similarities and differences were noted on comparison of the antinociceptive effects produced by anandamide (and the more potent fluroanandamide) and d9-THC [154], Anandamide was cross-tolerant to d9-THC, but in contrast to THC, it did not alter opioid-induced antinociceptive effects nor was its action blocked by a k antagonist. 

Raffa RB, Stone DJ, Hipp SJ (1999) Differential cholera-toxin sensitivity of supraspinal antinociception induced by the cannabinoid agonists delta9-THC, WIN 55,212-2 and anandamide in mice. Neurosci Lett 263 29-32... 

Anandamides can be produced with little investment (eg argon tank, a fatty acid) and yield unlimited quantities. Many of these fatty acid amides are CBl agonists and will replace both THC and cannabis. 

In addition to their short-term effects, cannabinoids also modulate the induction of long-term synaptic plasticity. Administration of THC and the endocannabinoids anandamide and 2-AG inhibits the induction of long-term potentiation (LTP) in the hippocampus (Nowicky et al. 1987 Terranova et al. 1995 Stella et al. 1997) and long-term depression (LTD) within the cerebellum and nucleus accumbens (Levenes et al. 1998 Hoffman et al. 2003a). 

A different, more complex learning protocol was used by Brodkin and Moer-schbacher (1997). In a specifically modified conditioning box, rats were trained for 14 weeks to respond to a sequence of lights by pressing appropriate keys. Once asymptotic performance criteria were met, drugs like cannabidiol (100 mg/kg) and anandamide (18 mg/kg) were injected, but had no effect on performance. By contrast. A THC (3.2-18 mg/kg) and R-(+)-methanandamide (1-18 mg/kg) impaired performance in a dose-related manner. This impairment was reversed by rimonabant (1 mg/kg), but the antagonist had no effect on its own. 

The above observations do not implicate the endothelium in the vasodilator response to anandamide. Other studies, which documented both endothelium-dependent and endothelium-independent components for the vasodilator effect of anandamide, confirmed the role of TRPVl receptors but only for the endothelium-independent component (Jarai et al. 1999 Mukhopadhyay et al. 2002). The endothelium-dependent vasodilator effect of anandamide in the rabbit aorta or the similar effect of abn-cbd in rat mesenteric arteries is unaffected by capsazepine (Mukhopadhyay et al. 2002 Jarai et al. 1999 Offertdler et al. 2003 Ho and Hiley 2003). Interestingly, sensory nerve terminals also appear to have CBi receptors, stimulation of which by very low doses of anandamide or by the synthetic cannabinoid HU-210, neither of which results in activation of TRPVl receptors, inhibits sensory neurotransmission (reviewed in Ralevic et al. 2002). Furthermore, a recent study by Zygmunt et al. (2002) indicates that THC and cannabinol, but not other psychotropic cannabinoids, can elicit CGRP release from periarterial sensory nerves by a mechanism that is independent of not only CBi and CB2 receptors, but also of vanilloid TRPVl receptors. Thus, the sensory nerve-dependent effects of cannabinoids are complex, as interactions with CBi and TRPVl receptors appear to have opposite functional consequences, and there may be additional actions independent of both of these receptors. TRPVl receptors are not involved in the dilation of isolated coronary arteries by anandamide either in the sheep, where the effect is endothelium dependent (Grainger and Boachie-Ansah 2001), or in the rat, where it is endothelium independent (White et al. 2001). Furthermore, in the rat mesenteric arterial bed, the role of sensory nerves and vanilloid receptors in the dilator effect of anandamide was found to be conditional on the presence of NO (Harris et al. 2002). 

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