Mar. 15, 2000 Researchers led by UCSF scientists are reporting that an experimental pain drug known as a kappa-opioid brings pain relief to female rats but not males, a finding that adds weight to a recent UCSF clinical finding, and highlights, they say, the need to evaluate drugs by gender.
Traditionally, kappa-opioids have been dismissed as ineffective analgesics in humans, though the drugs have shown mixed results in animal studies, depending on how they have been administered.
The finding, published in the March issue of Pain, may help to resolve the controversy about the drug's effectiveness, the researchers say, and underscores a weakness in traditional drug screening: Until the early 1990s, most drugs, including kappa-opioids, were primarily evaluated in men.
"The problem of gender differences, particularly in response to opioid drugs, is extremely important and widely under-appreciated," says the senior author of the study, Howard Fields, MD, PhD, a leading expert on the brain mechanisms of pain and a pain-treatment specialist. Fields is UCSF professor of neurology, a member of the Keck Center for Integrative Neuroscience and director of the UCSF Wheeler Center for the Neurobiology of Addiction.
"There may be classes of drugs that are particularly effective in women that don't have the side effects of currently available potent drugs," says Fields. "Kappas are an example, but it may be true for a lot of drugs and we just don't know it because we haven't looked. Drug companies might be throwing away a perfectly good drug because it doesn't work in males."
The specific finding is important because morphine, a class of opioid and the painkiller most often used for severe pain, has limitations - over time, people can develop tolerance to the drug and/or become dependent on it. As a result, researchers are intent on identifying an alternative class of opioids that lack the drug's limitations.
"A lot of people don't want to go on morphine because it is addictive," says Fields. "What if kappa agonists were non-addicting in females but were potent analgesics?"
The idea that males and females respond differently to opioids is not new, but until recently the difference was believed to be limited to potency, with clinical studies showing that women require less morphine for post-operative pain than men.
Fields' finding -- that specific brain regions in male and female rats have opposite reactions to kappa-opioids - suggests that the difference may be more fundamental, supporting clinical studies at UCSF that indicate kappa-opioids are more effective in women for clinically significant pain.
The original clinical study, led by UCSF professor Jon Levine, MD, PhD, showed that, in women, a drug made up of a diluted concentration of kappa-opioid had no effect, while a drug made up of a higher dose of the drug combination had a strong and lasting analgesic effect. In contrast, in men, the low dose actually increased pain; as the dose was increased, the heightened pain disappeared and a weak, short-lived analgesic effect set in.
The clinical finding was serendipitous. "The drug had been known for more than two decades and had simply been considered a bad analgesic," says Levine.
The discovery, he says, demonstrates a clear biological difference in the way women and men respond to kappa-opioids.
"If it weren't for the people data, I'd say, `who knows, a rat's a rat and our finding may have nothing to do with people,'" says Fields, "but taken together the findings have importance."
Fields' study pushes the investigation into the region of the brain where opioids bring about their analgesic effect, and puts researchers on track for determining the targets or mechanisms accounting for the contrasting responses.
The study also confirms the role of kappa-opioid in the contrasting analgesic responses. While Levine's team was restricted to using clinically available drugs that could have other effects, the Fields lab was able to use a drug that acted only at the kappa-opioid receptor.
The Fields investigators focused their study on a neural circuit in the brain that extends from a collection of pain-sensing neurons known as the ventrolateral periaqueductal gray (v1PAG) downward to another set, known as the rostral ventromedial medulla (RVM), and finally to a set in the spinal cord. This so-called "descending pathway" is the principal circuit through which opioids relieve pain in the body.
The nerve cells within the PAG and RVM structures are made up of pain-sensing cells that either transmit signals of pain or actively shut off pain. These so-called "on" and "off" cells, discovered by Fields, have opioid receptors on them. Opioids bring about pain relief by latching on to these receptors and setting into play a series of descending signals that first shut off, or inhibit, neurons that make pain worse and then, further down the circuit, exciting cells that shut off pain messages.
Morphine is one of a dozen drugs that target the so-called mu opioid receptor in the descending pathway. The kappa drug used in the study is one of several forms of kappa known to work at the kappa-opioid receptor. A major goal of current research efforts is to identify subtypes of opioid receptors that could provide targets for drugs that act like morphine without its side effects. The immediate goal of the current study was to tease out the impact that kappa-opioids have on the descending pathway of opioid pain relief.
Three years ago, the Fields team showed that treating the vlPAG neurons of male rats with a mu opioid brought about pain relief, but that subsequently adding kappa-opioid into the RVM markedly decreased the mu opioid's analgesic effect.
In the current study, the team observed the opposite response. Treating the vlPAG neurons of female rats with a mu opioid brought on the expected pain relief, but subsequently adding kappa-opioid into the RVM increased the mu opioid's analgesic effect.
"In males, kappa-opioid is somehow inhibiting the actions of mu opioid," says Fields.
One possible explanation, says Fields, is that the kappa receptors are acting on opposite types of neurons in males and females. In males, kappas may be inhibiting the so-called "off" nerve cells in the RVM that normally tell the spinal cord to shut off pain signals. In females, kappa-opioids actually excite the off neurons, which would relieve pain.
In their study, the researchers also discovered that female rats received significantly more pain relief when mu opioid was injected into the vlPAG than male rats, a fact that was not attributable to body weight or diffusion of the drug in the body.
This finding suggests, says Fields, that mu receptors in females also respond differently to mu opioids than they do in males. The ultimate explanation for the sexual dimorphism with respect to the mu and kappa-opioid receptors may prove to be hormonal, says Fields.
But regardless of the explanation, he says, "People need to understand that male and female brains are different, period. And this fact has to be taken into consideration when thinking about drug treatments, particularly drugs that act on the central nervous system."
The other co-authors of the Fields study were Sheralee A. Tershner PhD, formerly a post-doctoral fellow in the Fields lab and currently of the Department of Psychology, Western New England College, and Jennifer Mitchell, PhD, formerly a graduate student in the Fields lab.
The study was funded by the National Institute on Drug Abuse.
Notes: Opioids, which include morphine and heroin, originally derived from the juice of the opium poppy plant, and have been used for thousands of years to lessen pain and produce euphoria. They mimic naturally occurring forms of opioids -- the neurotransmitters known as endorphins and enkephalins - which act in the body in response to signals of pain, latching on to receptors on sensory nerve cells that normally receive and transmit pain signals.
Many people develop tolerance to morphine, but at very different rates, some over weeks, some over months.
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