**3.4. Vanilloid receptors**

to block inward rectifier potassium channels [58]. Moreover, administration of tertiapin in mice diminished the analgesic response evoked by spinal administration of high doses of morphine [59]. Further research in this area may result in better understanding of the pain modulation responses, managing drug addiction, and may lead to the discovery of new

Furthermore, voltage-gated Ca2+ channel activation directly affects membrane potential and contributes to the electrical excitability of neurons. Voltage-gated Ca2+ channels have an important role in the release of neurotransmitter from the presynaptic terminals in the dorsal horn in response to inward action potentials [60]. In this aspect, a peptide termed *N*-agatoxin isolated from the venom of the funnel web spider, and an American spider *Agelenopsis aperta* inhibits P/Q-type calcium channels that have been reported to play a role in migraine and headaches [61, 62]. Future research on the functional role of P/Q-type calcium channels may

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

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 anti-

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

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 deriva-

provide an additional target for the modulation of pain responses.

analgesic compounds.

290 Pain Relief - From Analgesics to Alternative Therapies

**3.2. Acetylcholine receptors**

Mamba snake toxins [3].

nociceptive pathways [64].

**3.3. Cannabinoid receptors**

peripheral nerve terminals and on mast cells [65].

tive as an endogenous cannabinoid substance [67].

Vanilloid receptors (VR), or vanilloid-gated ion channels, also known as capsaicin receptors, have been shown to be involved in nociception [69]. Nonetheless, their clinical potential remains to be proven. Vanilloid receptors are expressed almost exclusively by primary sensory neurons involved in nociception and neurogenic inflammation.

It is well established that the VR agonists give rise to excitatory effects characterized by nociception and neurogenic inflammation, followed by desensitization [14, 70]. Notably, many natural products are known as modulators of these receptors. Capsaicin, for example, is a VR1 receptor agonist and is marketed in the United States in topical preparations for the treatment of arthritis and inflammatory joint pain. At the present time, it is believed that VR1 receptor agonists can be good attractive therapeutic target. Interestingly, other "hot" spices, like piperine and zingerone, the active ingredients in black pepper and ginger, respectively, also appear to act through VR activation [71].

Peripheral fibres are the site of release of a variety of neuropeptides among which substance P (SP) and calcitonin gene-related peptide (CGRP) are defined. Depletion of SP and CGRP as well as of vanilloid receptors occurred following treatment with capsaicin, in the spinal and peripheral terminals of capsaicin sensitive neurons in almost 24 h [28].

Other naturally occurring compound acting at VR1 receptors is of fungal origin, a triprenyl phenol, termed scutigeral, a novel structural class of VR ligand. Scutigeral, isolated from the non-pungent edible mushroom *Albatrellus ovinus*, has been shown to stimulate rat dorsal root ganglion neurons by activation of vanilloid receptors [72].
