Experimental Pharmacology

Cannabinoids and Thermoregulation

One of the characteristic pharmacological properties of CB1 receptor agonists is an ability to induce hypothermia (Pertwee 1985). The changes of body temperature caused by cannabinoids are dose dependent. According to Pertwee, higher doses of THC cause hypothermia by lowering the thermoregulatory set point, while lower doses are hyperthermic. It has been postulated that differential Gs and Gi protein activation by CB1 receptors could explain these findings (Sulcova et al. 1998)....

CB1 and CB2 Cannabinoid Receptor Ligands

In terms of chemical structure, established cannabinoid receptor agonists fall essentially into four main groups classical, nonclassical, aminoalkylindole and eicosanoid (reviewed in Howlett et al. 2002 Pertwee 1999a). - The classical group consists of dibenzopyran derivatives that are either cannabis-derived compounds (phytocannabinoids) or their synthetic analogues. Notable examples are the phytocannabinoids49-THC,48-THC and cannabinol (Fig. 1), and the synthetic cannabinoids,...

Constitutive Activity

Overexpression of many GPCRs leads to some degree of constitutive (agonist-independent) activity (Lefkowitz et al. 1993). Experimental evidence for consti-tutively active CB1 receptors was first noted when SR141716A, initially described as a CB1 antagonist, was found to have inverse agonist properties (Bouaboula et al. 1997). In transfected CHO cells expressing CB1, cannabinoid agonists activated mitogen-activated protein kinase (MAPK) activity (Bouaboula et al. 1997). However, basal MAPK...

Cannabinoid CB1 Receptor Antagonists Inverse Agonists

The first CB1 antagonist, SR141716A (7) was developed by Rinaldi-Carmona and co-workers at Sanofi Recherche (Rinaldi-Carmona et al. 1994). SR141716A displays nanomolar CB1 affinity (K 1.98 13 nM), but very low affinity for CB2. In vitro, SR141716A antagonizes the inhibitory effects of CB agonists on both mouse vas deferens contractions and adenylyl cyclase activity in rat brain membranes. SR141716A also antagonizes the pharmacological and behavioral effects produced by CB1 agonists after...

Neurotransmission via Monoamines and Acetylcholine

A synopsis of the inhibitory effects of cannabinoids on the release of the monoamines noradrenaline, dopamine and serotonin and of acetylcholine in the brain and the retina is given in Table 3. Noradrenaline release is inhibited via CB1 receptors in the hippocampus of guinea-pig and man but not in the hippocampus of rat and mouse (Table 3, Fig. 4 Van Vliet et al. 2000). Although CB1 receptors inhibit the release of dopamine from amacrine cells of the retina, contradictory results were obtained...

Phenotypes of Dorsal Root Ganglion Cells Expressing CB1Rs and CB1R mRNA

To better understand the role of cannabinoids in sensory processing, phenotypes of dorsal root ganglion cells that synthesize CBIRs have been investigated by several laboratories (Ahluwalia et al. 2000, 2002 Bridges et al. 2003 Hohmann and Herkenham 1999b Price et al. 2003). Small-diameter cells in the dorsal root ganglia, in general, correspond to nociceptors and thermoreceptors, respond to high-threshold stimuli, and have unmyelinated or thinly myelinated axons. The small-diameter cells fall...