A drug that enhances the effectiveness of prescription painkillers, while reducing their addictiveness and cutting chronic pain may be on the horizon, if a new line of animal research pans out.
A recent study, published in the Journal of Neuroscience, found that when rodents were given a drug called (+)-naloxone — which is a mirror-image molecule of the drug naloxone, an overdose antidote — along with opioid drugs like morphine they did not display the typical signs of addiction, such as self-administering the drug or developing a preference for the place that they received it. Such behaviors typically occur when rats and mice are exposed to the same kinds of drugs that people tend to enjoy that have a potential for addiction. When these behaviors don’t manifest, it suggests that the animals aren’t feeling pleasure from the drugs.
Most surprisingly, while (+)-naloxone blocked the high from opioids, it enhanced the drugs’ pain-relieving effect. Many previous attempts to dissociate these characteristics of opioids in the brain have failed, leading researchers to believe it wasn’t possible. But the new research suggests it is — it’s just that until now, scientists may have been looking at the wrong pathways in the brain. The new study indicates that the high and most of the negative effects of opioids, such as tolerance and withdrawal, are actually caused by immune cells in the brain — not the neurons involved in pleasure and pain.
“This is a paradigm shift in how one views drug reward,” says lead author Linda Watkins of the University of Colorado, Boulder. “All prior concepts of why drugs like opioids are rewarding, why drugs become abused, have focused exclusively on neurons.”
While cautioning that the overall significance of the findings cannot yet be assessed, pioneering opioid researcher Dr. Gavril Pasternak of New York’s Memorial Sloan-Kettering Cancer Center said that the new work “opens a new area of study and potential insights that are important.” He was not associated with the research.
Neuroscientists tend to focus on the function of neurons, the nerve cells that are responsible for transmitting information throughout the brain. But about 90% of brain tissue is actually made of immune cells called glia, whose actions are less clearly understood and have often been considered mere “support” cells that lack important roles in emotion, perception or thought. Increasingly, however, studies like this suggest otherwise.
The study drug, (+)-naloxone, acts on glia, blocking a type of receptor called toll-like receptor 4 (TLR4), which is found on glial cells. Activation of this receptor appears to be important for both the pleasure and dependence-producing effects of opioids: when the receptor was blocked by (+)-naloxone, rodents didn’t seek opioids or become tolerant to them. Blocking this receptor also enhanced opioids’ pain-relieving power.
But while giving (+)-naloxone to block TLR4 seemed to mitigate the development of opioid tolerance and withdrawal, mice that were bred to lack the TLR4 receptor altogether still experienced some withdrawal symptoms when opioids were stopped, suggesting that the function of the receptor doesn’t fully account for opioid dependence.
Here’s how the system may work: when exposed to opioid drugs like morphine, glial cells become active; in turn, they ramp up the activity of the neurons that respond to opioids, which are critical to pathways involved in pleasure and pain, explains Watkins. When this activity occurs in a pain pathway, glial activation amplifies pain. This counteracts what the opioid is “trying” to do for pain control, she says; morphine suppresses pain by acting on neurons, but it simultaneously enhances pain by activating glia. But since the morphine suppression is typically greater than the glial activation, the drug cuts pain overall.
Over time, with continue use of painkillers, however, glia become increasingly activated — that’s what reduces the drugs’ pain-relieving effect, producing tolerance and the need for larger and larger doses.
The same holds true for the neurons involved in opioid-related pleasure, according to Watkins; glial activation revs up the neurons, “but now the neurons are in the reward pathway so you get amplification of reward,” she says. “You can think of glia as volume controls. They can dial up pain. They can dial up drug reward.”
And (+)-naloxone seems to turn glia down. Some types of chronic pain may in fact be caused by inflammation related to glia turning up pain circuits; earlier research by Watkins and colleagues has shown that (+)-naloxone can also counteract this type of pain, at least in rodents.
So far, (+)-naloxone has not been tested on humans. However, another drug that blocks TLR4 has undergone early stage clinical testing for use in addiction treatment to reduce withdrawal symptoms and block the opioid high. That drug, ibudilast, is already approved for other uses in Japan.
Potentially, ibudilast or a drug like (+)-naloxone could be added to prescription painkillers like OxyContin to increase pain relief, prevent the high and mitigate the development of tolerance and withdrawal upon cessation of use. “Combinations are an interesting possibility,” says Pasternak, adding that there’s not enough data yet to know whether they would work.
Also, it is not clear whether preventing the high would hinder certain aspects of pain relief in humans. Subjective experiences of opioid use suggest that the “high” — the relief of anxiety and sense of distance from the pain — is not totally separate from the actual physical pain relief, and multiple previous efforts to dissociate the two have failed.
By itself, however, (+)-naloxone or a similar drug could be developed to treat chronic pain. “We are trying to [raise the funds to] start a company to take this to clinical trials,” says Watkins. “There is a huge unmet need for effective therapies for chronic pain.”
Of course, the long history of the quest for non-addictive opioids is one of repeated failure. Heroin was supposed to be a less addictive form of morphine, and OxyContin was supposed to be a less addictive pain reliever, too. But these new immune system connections are only just beginning to be explored — and they may open up many new possibilities for relief.