The Contribution of cocoa additive to cigarette smoking addiction

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 -