The Contribution of cocoa additive to cigarette smoking addiction

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Page 178 of 207 RIVM report 650270002 Anandamide TWAD =MAK: No data available. TWAUSA: No data available. STELNL: No data available. STELUSA: No data available. LTEL: No data available. TLV-C: No data available. TLV-CARCINOGENICITY: No data available. MAK-REPRODUCTION: No data available. Others: Reference value: Endocannabinoid-like compounds, such as anandamide were determined in human brain. Anandamide level was 56 ± 17 ng/mg protein, which represented 7.7% of total endocannabinoid-like compounds (7). No data are available on blood anandamide level of normal human subjects. However, some data are available on blood anandamide level of pregnant women by IVF-embryo transfer. The anandamide blood level was higher in women who failed to achieve an ongoing pregnancy than in those who became pregnant (1.4 ± 0.8 ng/ml and 0.3 ± 0.3 ng/ml, respectively) (8). Anandamide was determined in plasma prepared from rat blood collected either by cardiac puncture or by decapitation. After cardiac puncture, anandamide level was1.1 ± 0.2 ng/ml (mean ± sem, n = 9). By contrast, after decapitation anandamide was dramatically elevated (50 ± 4.5 ng/ml) (9). Anandamide level, measured in deproteinated rat blood plasma, was 1.8 ng/ml (10). CLASS EG Carc. Cat.: No data available. IARC-category: No data available. CEC: No data available. Critical assessment On the assumption that anandamide is not degraded during tobacco processing and cigarette combustion, the exposure level of anandamide through cigarette smoking is 12.5 ng/day (at smoking 25 cigarettes per day). Due to lack of data, the exposure through cigarette smoking can not be compared with environmental anandamide exposure. By comparing the anandamide exposure through cigarette smoking with the endogenous anandamide level in human brain and blood (56 ng/mg protein and 1.4 µg/l, respectively), it can be concluded that anandamide level in cigarette is significantly lower than the endogenous pool. No data are available on the pyrolysis/combustion products of anandamide. Conclusion The anandamide exposure through cigarette smoking is significantly lower than the endogenous anandamide level in human subjects. However, no conclusion can be drawn on the local anandamide exposure on the respiratory system and this might be a point of concern.
RIVM report 650270002 Page 179 of 207 Anandamide PHARMACODYNAMICS Mechanism of action Cannabinoid receptors, the molecular targets of the active principle of cannabis ∆ 9 - tetrahydrocannabinol, are activated by a small family of naturally occuring lipids that include anandamide (11). Two cannabinoid receptors have been identified to date; CB1 and CB2. These are G-protein coupled receptors (12). The CB1 receptor and its splice variant CB1A, are found predominantly in the brain with highest densities in the hippocampus, cerebellum and striatum. Considerably lower expression is found in peripheral tissue including lung, testis, uterus and vascular tissue. The CB2 receptor is found predominantly in the spleen and in haemopoietic cells and has only 44% overall nucleotide sequence identity with the CB1 receptor. Following agonist binding, the CB1 receptor mediates inhibition of adenylate cyclase, inhibition of N- and P/Q-type calcium channels, stimulation of potassium channels, and activation of mitogen-activated protein kinase. The CB2 receptor mediates inhibition of adenylate cyclase and activation of mitogen-activated protein kinase. Anandamide is released from neurons upon depolarization through a mechanism that requires calcium-dependent cleavage from a phospholipid precursor in neuronal membranes. The release of anandamide is followed by rapid uptake into the plasma and hydrolysis by fatty-acid amidohydrolase.The psychoactive cannabinoids increase the activity of dopaminergic neurons in the ventral tegmental area-mesolimbic pathway (13). Other effects of anandamide that are not mediated via cannabinoid receptors include inhibition of L-type Ca 2+ channels, stimulation of vanilloid receptors (VR1), transient changes in intracellular Ca 2+ , and disruption of gap junction function. Activation of VR1 receptors by anandamide causes release of calcitonin-gene-related-peptide (14). Pulmonary system breathing frequency: see airway resistance. tidal volume: see airway resistance. lung compliance: see airway resistance. airway resistance: Anandamide was tested for bronchodilator activities. Conscious guinea pigs were given cumulative i.v. doses of anandamide (1.0, 3.0, and 10.0 mg/kg) to assess its effect on dynamic compliance (C-dyn), total pulmonary resistance (R-L), tidal volume (V-T) and breathing frequency (f). Anandamide did not significantly affect C-dyn, R-L, V-T and f. These results suggest that in vivo anandamide has minimal direct airway smooth muscle-related actions (15). Calignano et al. (1990) postulated that activation of CB1-receptors by locally released anandamide may participate in the control of bronchial contractility. How anadamide exerts such a control may depend, however, on the state of the bronchial muscle. When the bronchospasm was induced by capsaicin (intratracheal, ± 67 % of the maximal bronchoconstriction) in anaesthitized guinea-pigs , then anandamide produced a dose-dependent (0.5 –5mg/kg, i.v.) attenuation of the induced-bronchospasm (eliminated the bronchospasm at 5 mg/kg). Anandamide (5 mg/kg, i.v.) had no direct bronchomotor action (11.8 % of maximal bronchoconstriction). After vagotomy, systemic application of anadamide produced a dose-dependent bronchoconstriction in guinea-pigs (the highest dose, 5 mg/kg i.v., exerted ± 55% of the maximal bronchoconstriction) (16). Another study showed that sensory nerves innervating blood vessels play a role in the local and systemic regulation of the cardiovascular and respiratory (CVR) systems. The CVR reflexes evoked by administration of anandamide (75 -
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