**3.2. Acetylcholine receptors**

Two classes of acetylcholine receptors are well-known, the muscarinic and the nicotinic acetylcholine receptors. Both classes were recognized through the utilization of the natural products, muscarine and nicotine, respectively. The role of these receptors in modulating the central nociception has been well-documented. The muscarinic acetylcholine receptors have several known natural product ligands including: hyoscyamine, atropine, scopolamine and Mamba snake toxins [3].

Epibatidin, an alkaloid isolated from the skin of the Ecuadorian dart-frog, *Epipedobates tricolor*, has been reported to be a potent nicotinic analgesic. It could be antagonized by mecamylamine, a nicotinic receptor antagonist [63]. Accordingly, it was established that epibatidine as a powerful tool for studying nicotinic pathways involved in pain perception. As well, its remarkable efficiency as an antinociceptive may be due to the selective effects on central antinociceptive pathways [64].

## **3.3. Cannabinoid receptors**

Two cannabinoid receptors, CB1 and CB2, have been identified and subsequently cloned. They belong to G-protein coupled receptors family, sharing 44% amino acid sequence homology but vary in their anatomical distribution. Expression of CB1 receptor is mainly in the CNS and to a lesser extent in other tissues, while CB2 receptor is primarily expressed in peripheral tissues associated with immune functions, including macrophages, B and T cells, as well as in peripheral nerve terminals and on mast cells [65].

The endogenous family of ligands that interact with these receptors is known as the anandamides (*N*-arachidonoyl-ethanolamine). They are lipid in nature with antinociceptive activity but not as potent as tetrahydrocannabinol (THC) [66]. Interestingly, neurons in the brain produce, release and inactivate anandamide, confirming a role for this arachidonate derivative as an endogenous cannabinoid substance [67].

Remarkably, a nonnitrogenous lipophilic molecule, Δ<sup>9</sup> -tetrahydrocannabinol (Δ<sup>9</sup> -THC), isolated from *Cannabis sativa*, is the prototypical ligand, interacting with the cannabinoid G-protein coupled receptors [68]. It has also been reported that another constituent cannabidol isolated from *C. sativa* exerts important anti-inflammatory activity. Cannabinoid receptor agonists induce a number of unwanted CNS effects, which are supposed to be mediated mainly by the central distribution pattern of CB1 receptors [65].
