Nicotine was known offer mild pain relief for years, and this effect arises from the binding of nicotine to acetylcholine receptors around the body, however, this was no use as a medication due to the all too ubiquitous reminders of the health risks this drog poses.

Acetylcholine is a very widespread neurotransmitter, and there are 2 types of acetylcholine receptors, nicotinic and muscarinic. Epibatidine acts on the nicotinic receptors, which are present all over the nervous system and affect everything from neuromuscular junctions to the autonomic nervous system, which unconsciously controls internal organs.

When nicotine binds to the receptor, it is an agonist, i.e. it performs the same function as the natural neurotransmitter. Agonists for nicotinic receptors have come into recognition for being possible drugs against Alzheimer's, Parkinson's and chronic pain, as all these involve the acetylcholine pathway.

The promise of epibatidine as an analgesic began with the very first hotplate and tail-twitching pain experiments on mice. The spectroscopic data showed the similarity between the structures of epibatidine and nicotine with both sharing the pyridyl ring. This similarity was what first suggested nicotinic receptors as a mode of action of the toxin. Investigations with mice have since shown that epibatidineis not only selective for nicotinic receptors in the brain, but for neuromuscular nicotinic receptors as well.

The nicotinic receptors in the brain are involved in pain suppression and provide very strong analgesia, but with none of the side effects of morphine. Mice given doses of morphine, then taught to press a switch to administer more does will continue to press the switch with increasing frequency, even when there was no source of pain. When this experiement was repeated with epibatidine, the mice showed no sign of either addiction or tolerance and did not press the switch when in no pain.

However, epibatidine also bound very strongly to the neuromuscular receptor in which acetylcholine regulates muscle contraction and relaxation. By binding to these, epibatidine causes paralysis, and can kill if the muscles of the lungs and respiratory system become depressed.

Chemically, epibatidine would bind more effectively to the receptor as the NH on the bicyclic ring would provide better hydrogen bonding, therefore more intermolecular forces of attraction to the protein.

This side effect means epibatidine is useless itself as an analgesic, but by producing an epibatidine derivative which would be selective only for the nicotinic receptors in the brain, and not those at the neuromuscular junction, a new class of painkiller would be released. Current research into derivatives continues.

The acetylCholine receptor

The 3D model shows the receptor, which spans the membrane of the neurones.