**3.1. Voltage-gated ion channels**

Following oral intake, maximum plasma concentration arises between 30 min and 2 h, which may be prolonged with food ingestion. Caffeine is readily absorbed by the gastrointestinal tract, with 100% bioavailability and high solubility both in aqueous and nonpolar organic solvents. Caffeine is lipophilic with low protein binding. Its plasma protein binding—mainly albumin—is 10–35%. Caffeine rapidly crosses cell membranes, as well as the placental barrier, blood brain, producing drug levels in the brain and cerebrospinal fluid similar to those in

In 1985, Burnstock and Kennedy cited that methylxanthines block purinergic receptors type 1 (P1) and have no effect on P2 receptors [50]. Added to that, the proposed mechanism of action of caffeine seems to be related to the blockade of peripheral and central adenosine receptors involved in the regulation of pain transmission, giving rise to its analgesic properties [14, 51].

Ginseng, the root of *Panax ginseng* (*Araliaceae*), has been reported to relieve a variety of ailments. Studies showed that ginseng saponins, which consist of various ginsenoids (**Figure 18**), are the most pharmacoactive constituent of ginseng root. Ginsenoids are believed to be involved in

In traditional folk medicine, ginseng has been used to relieve some types of pain such as toothache, abdominal pain, chest pain and neuralgia. A line of evidence also shows that ginseng

pain modulation as well as in opioid-induced antinociception and tolerance [52, 53].

plasma [46, 49].

**Figure 17.** Theobromine.

288 Pain Relief - From Analgesics to Alternative Therapies

**2.7. Ginsenosides**

**Figure 18.** Ginsenosides.

Many natural products have been found to interact with voltage-gated ion channels. Some more recent natural products are to be studied at the Na+ , K+ and Ca2+channels. These compounds cause their effects through several mechanisms of action.

Voltage-gated Na<sup>+</sup> channels play a central role in the generation and dissemination of action potentials in neurons and other cells such as skeletal muscle and cardiac cells. Modulators of sodium channels are being used as local anaesthetics, antiarrhythmics, analgesics and antiepileptics, and for other disorders [56]. In this aspect, tetrodotoxin, isolated from the puffer fish, blocks sodium channels and causes great harm to those that ingest it leading to numbness in the lip and tongue within 20 min of ingestion followed by paralysis and may cause death. Consequently, the use of tetrodotoxin as a key compound for analgesic development has been limited by its toxic nature [3].

As well, voltage-gated K+ channels have been shown to be involved in pain processes. Activation of potassium channels leads to membrane hyperpolarization then inhibition of cell excitability. Those pain signals may be transmitted either directly or indirectly depending on the location of these channels. Today, several anaesthetics are used clinically to work through interactions with potassium channels [57]. Certain peptides from natural sources have been identified to act through potassium channels. For instance, tertiapin, a peptide with 21 amino acids, isolated from the venom of the honey bee, has been shown 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 analgesic compounds.

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 provide an additional target for the modulation of pain responses.
