http://www.biosciencetechnology.com/news/2015/10/nicotine-increases-codeine-relief-could-mean-risk-addiction
Nicotine increases the amount of a specific enzyme in the brain that may increase the speed codeine is converted to morphine in the brain, according to research from the University of Toronto. The findings could implicate that smokers are at a higher risk for addiction to codeine.
Researchers, led by Rachel Tyndale, Ph.D., professor of pharmacology, toxicology, and psychiatry at the University of Toronto, administered codeine to rats in four groups and measured both their pain relief and levels of codeine and morphine.
The first group received nicotine for one week before receiving codeine; the second group was given an inhibitor, propranolol, which blocks the activation of codeine; the third group received both nicotine and the inhibitor, while a fourth control group was given neither.
The rats that received only nicotine had substantially more morphine in their brain and experienced greater pain relief, than those who also received the inhibitor. The group that was given propranolol and not nicotine had the lowest levels of pain relief and brain morphine. All of the groups maintained the same level of morphine in the blood, which showed it was change in the activity of the enzyme within the brain, not the liver that determined the effect of codeine on pain relief.
The biggest take away from the study, published earlier this year in Neuropsychopharmacology, “is there is genetic and environmental influences on the effects of drugs of abuse,” Tyndale, who is also senior scientists in the Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health (CAMH), told Bioscience Technology. “In this case both those with faster activation of codeine to morphine, within the brain, due to genetics or due to induction of the enzyme, likely have better pain control, but also more risk for addiction to codeine. The latter group includes smokers. More generally it suggests that metabolism of drugs within the brain may alter the abuse potential for drugs.”
In the team’s preclinical mouse model, they showed that chronic nicotine increases the level of the enzyme in the brain which activates codeine to morphine. “We know this as we observe more of the enzyme in the brain in animals treated with nicotine, and in the brains of smokers in autopsy tissues,” Tyndale told Bioscience Technology. “When there is more of the enzyme in the brain, what we have shown is that codeine gets activated to nicotine more quickly and more extensively, increasing the pain relief from codeine by creating more morphine.”
This is a new way of looking at the brain’s role, as a more active participant, with codeine not just metabolized in the liver, but also in the brain itself.
“This is opening up a whole new area of research and potentially a substantial source of variation between people in their response to drugs and toxins acting on the brain,” Tyndale said. “We’re starting to see patterns and relationships, like the nicotine and codeine connection. This is also of interest in drug development as we might be able to create drugs that are only activated once they get to the brain.”
A limitation of the study is that it is a preclinical animal model. While the researchers know that the enzyme is higher in the brains of smokers, they still need to demonstrate that the brain enzyme is important to the effects of codeine in people.
Up next, the team plans to look at other opiates such as oxycodone, and hydrocodone, Tyndale said, “which are also metabolized by the same enzyme to determine what the effect of metabolism in the brain is for these other drugs.” They are also planning translational studies to take the work into humans.