By David N. Leff

Can tobacco feel your pain?

¿Australian aborigines,¿ observed molecular neurobiologist Imad Damaj, ¿used to use nicotine-containing plants at high doses for their analgesic [pain-dulling] effects.¿ But you won¿t find nicotine alongside morphine on the shelf of pain-management drugs.

¿People smoke tobacco,¿ Damaj pointed out, ¿not for pain relief but for nicotine¿s other behavioral effects. They smoke to handle stress, to get psychological reinforcement, to decrease anxiety ¿ because nicotine is a known anxiolytic ¿ and also because it helps users cope with anxiety. But it¿s very hard to say that people are smoking for the pain-modulating effect.¿

As for employing nicotine per se in pain management, Damaj continued, ¿Nicotine itself is not used as an analgesic, although it does have weak to moderate analgesic effects in human beings and in animals. What limits nicotine in the human is its toxic side effects. As you go a little bit high in dose you start seeing cardiovascular and gastrointestinal disturbances, seizures and other bad side effects.¿

Nicotine gets in its anti-pain licks via a network of customized receptors throughout the central and peripheral nervous systems. Damaj, at the Medical College of Virginia Commonwealth University, in Richmond, specializes in the neuropharmacology of nicotine. He explained:

¿Nicotine receptors in the brain and spinal cord ¿ the neuronal acetyl choline nicotinic receptors ¿ are a family of ligand-gated ion channels. Those channels,¿ he went on, ¿are formed of five subunit proteins. These get together and assemble to form a pore in the membrane of the neuron. And those different subunits ¿ alpha and beta ¿ can either come together as a hetero complex, like an alpha getting with a beta, or as a homo complex, five alphas getting together. But beta subunits by themselves can¿t form receptors.

¿Practically speaking, nowadays,¿ he pointed out, ¿we really don¿t know the real structure of the naked nicotinic receptor, but we have a good idea that there are at least three to four different subtypes in the brain. One of them is a combination of what we call alpha4 and beta2 subunits.¿

Damaj is a co-author of a paper in today¿s Nature, dated April 29, 1999, titled: ¿Reduced antinociception in mice lacking neuronal nicotinic receptor subunits.¿ Its senior author is molecular neurobiologist Jean-Pierre Changeux at the Pasteur Institute in Paris.

In previous work, Changeux had suggested the possible contribution to nicotine analgesia of the widely expressed alpha4 and beta2 subunits. So he and his co-authors generated two lines of knockout mice, one lacking alpha4, the other, beta2. They tested each strain¿s tolerance to pain before and after injection with nicotine, morphine or epibatidine (a potent nicotine agonist, or surrogate).

As is routine in such in vivo studies, the researchers laid on thermal pain by one of two testing methods ¿ the hot plate and the hot tail-flick.

When a mouse is placed on the hot plate, which is held at a steady 55 degrees Celsius (131 degrees Fahrenheit), Damaj said, ¿its tail is not in contact with the heat source. When the animal feels the heat, its reaction is to jump, or thump its hind paw rapidly, or lick it.¿

In the alternative tail-flick trial, a light bulb shines its heat on the mouse¿s tail until it flicks it ¿ a signal that the burn hurts.

¿The hot plate and tail-flick,¿ Damaj pointed out, ¿are both acute pain stimuli. We found that when you use the hot plate, you are involving a supraspinal brain area. It doesn¿t mean you are not involving the spinal cord, too, but the major involvement is in the supraspinal side of the brain. We were, in a way, surprised to find this association.

¿There is evidence,¿ Damaj added, ¿suggesting that there is more involvement of the spinal area. In a way, what we were measuring here, grosso modo, was a supraspinal response and a spinal reflex response. In our hands, we discovered that in the supraspinal one there is a big involvement of alpha4 and beta2 receptor subunits.

¿In the spinal reflex one,¿ he continued, ¿there is only partial involvement of alpha4, beta2, suggesting that on that side other subunits are involved.¿

Both knockout mouse strains evinced no pain-modulating effect of nicotine, a non-opioid, but still responded to the opioid morphine as a highly effective analgesic, indicating that these two classes of pain reaction act through different neuronal pathways. Even more to the point, the experiments showed that alpha4 and beta2 subunits mediate nicotine analgesia.

¿Nicotine acts on its different receptor sites in the brain in a non-discriminatory way,¿ Damaj observed. ¿In other words, there is no selectivity in its effects. So, if you can develop a compound that has more selectivity, that activates the good receptors and leaves out the receptors that could cause adverse side effects, you definitely will get a good anti-pain drug.¿

Abbott Testing Nicotine Agonist As Painkiller

¿In a way,¿ he mused, ¿it recalls what the Abbott people call ABT594, their nicotinic analgesic drug, which is in clinical trials now. Their approach minimizes the bad effect and maximizes the beneficial effect.¿

Anent that novel drug, in Phase II trials by Abbott Laboratories, of Abbott Park, Ill., the Nature paper¿s first author, neuropathologist postdoctoral fellow Lisa Marubio, told BioWorld Today:

¿There has been some recent interest in nicotine as an analgesic. Not nicotine itself, because it has toxic side effects. However, the compound epibatidine has been shown to be 200 times more potent against pain than morphine. And the new compound, ABT594, which just came out from Abbott last year, with a structure based on epibatidine, is also reportedly 200 times more potent than morphine.

¿ABT594 is an exciting drug compound,¿ observed Marubio, who moved to Changeux¿s group in Paris from the University of Chicago. ¿This drug does indeed avoid the toxic cardiovascular effects of nicotine, and acts as a potent analgesic. So our finding can help to discover compounds that target these receptors while avoiding the toxic effects of nicotine.¿

¿We already have several compounds of interesting profile,¿ Damaj observed, ¿one of them patented as an analgesic. In our hands, and the Abbott group¿s,¿ he concluded, ¿animal studies show that nicotine is indeed active in chronic neuropathic and arthritic pain models.¿ n