A new painkiller made by adapting the body’s naturally occurring opioids could provide a safer, non-addictive alternative to current analgesic drugs, with far fewer side-effects than those produced by morphine.
Opioids are natural or synthetic compounds that bind to the opiate receptors in the brain and central nervous system in order to numb feelings of pain. At present, the most effective painkilling drugs are those that act on the mu opioid receptor (MOR), with morphine being among the most common of these. However, many of these substances also cause damaging side effects, negatively affecting breathing and motor coordination as well as being highly addictive.
Endogenous opioids – meaning those that occur naturally within the body – such as endomorphin help to biologically regulate pain, although most previous attempts to harness them for the production of new drugs have ended in frustration. This is largely due to their linear structure, which makes them somewhat unstable.
However, a team of researchers from Tulane University has managed to produce a number of endomorphin variants with improved stability and solubility, by converting them into a ring structure. When administered to rats these variations, or analogs, produced significant reductions in the six major side effects associated with morphine, at doses that yielded the same analgesic effects.
For instance, by placing the rats on a rotating rod and observing their ability to maintain balance, the researchers noted that subjects displayed impaired motor coordination after receiving morphine but not when they received these endomorphins. Additionally, they found that the rats’ breathing was not disrupted by the endomorphins as it was by morphine, while further tests showed that glial activation was also avoided by the new compounds.
Glial cells are involved in the amplification of pain and can become overactivated by morphine, meaning regular users often suffer from hyperalgesia, whereby their regular responses to painful stimuli are intensified without the drug. This contributes to the addictiveness of morphine, although rats were found to exhibit greatly reduced levels of hyperalgesia when treated with endomorphins instead.
While all of the endomorphin analogs generated some degree of reduction in side effects compared to morphine, one in particular – known simply as analog 4 – was found to be superior to all others. Among the reported benefits of this compound is a markedly decreased potential for abuse, highlighted by the way in which rats did not become addicted to it.
To test this, the rats were trained to press a button in order to receive analgesic drugs. When morphine was used in this experiment, rats continually increased the rate at which they pressed the button as dependence set in, although this effect was completely absent when analag 4 was used.
A report of these experiments has been published in the journal Neuropharmacology, and the researchers now hope to begin clinical trials using human subjects within the next two years.
