Researchers led by UCSF scientists are reporting that an experimental pain drugknown as a kappa-opioid brings pain relief to female rats but not males, afinding 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 inhumans, though the drugs have shown mixed results in animal studies, dependingon how they have been administered.
The finding, published in the March issue of Pain, may help to resolve thecontroversy about the drug's effectiveness, the researchers say, andunderscores 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 ofthe study, Howard Fields, MD, PhD, a leading expert on the brain mechanisms ofpain and a pain-treatment specialist. Fields is UCSF professor of neurology, amember of the Keck Center for Integrative Neuroscience and director of the UCSFWheeler Center for the Neurobiology of Addiction.
"There may be classes of drugs that are particularly effective in women thatdon'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'tknow it because we haven't looked. Drug companies might be throwing away aperfectly good drug because it doesn't work in males."
The specific finding is important because morphine, a class of opioid and thepainkiller most often used for severe pain, has limitations - over time, peoplecan 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 lackthe drug's limitations.
"A lot of people don't want to go on morphine because it is addictive," saysFields. "What if kappa agonists were non-addicting in females but were potentanalgesics?"
The idea that males and females respond differently to opioids is not new, butuntil recently the difference was believed to be limited to potency, withclinical studies showing that women require less morphine for post-operativepain than men.
Fields' finding -- that specific brain regions in male and female rats haveopposite reactions to kappa-opioids - suggests that the difference may be morefundamental, supporting clinical studies at UCSF that indicate kappa-opioidsare more effective in women for clinically significant pain.
The original clinical study, led by UCSF professor Jon Levine, MD, PhD, showedthat, in women, a drug made up of a diluted concentration of kappa-opioid hadno effect, while a drug made up of a higher dose of the drug combination had astrong and lasting analgesic effect. In contrast, in men, the low dose actuallyincreased pain; as the dose was increased, the heightened pain disappeared anda weak, short-lived analgesic effect set in.
The clinical finding was serendipitous. "The drug had been known for more thantwo decades and had simply been considered a bad analgesic," says Levine.
The discovery, he says, demonstrates a clear biological difference in the waywomen 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 ourfinding may have nothing to do with people,'" says Fields, "but taken togetherthe findings have importance."
Fields' study pushes the investigation into the region of the brain whereopioids bring about their analgesic effect, and puts researchers on track fordetermining the targets or mechanisms accounting for the contrasting responses.
The study also confirms the role of kappa-opioid in the contrasting analgesicresponses. While Levine's team was restricted to using clinically availabledrugs that could have other effects, the Fields lab was able to use a drug thatacted only at the kappa-opioid receptor.
The Fields investigators focused their study on a neural circuit in the brainthat extends from a collection of pain-sensing neurons known as theventrolateral periaqueductal gray (v1PAG) downward to another set, known as therostral ventromedial medulla (RVM), and finally to a set in the spinal cord.This so-called "descending pathway" is the principal circuit through whichopioids relieve pain in the body.
The nerve cells within the PAG and RVM structures are made up of pain-sensingcells that either transmit signals of pain or actively shut off pain. Theseso-called "on" and "off" cells, discovered by Fields, have opioid receptors onthem. Opioids bring about pain relief by latching on to these receptors andsetting into play a series of descending signals that first shut off, orinhibit, 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 receptorin the descending pathway. The kappa drug used in the study is one of severalforms of kappa known to work at the kappa-opioid receptor. A major goal ofcurrent research efforts is to identify subtypes of opioid receptors that couldprovide targets for drugs that act like morphine without its side effects. Theimmediate goal of the current study was to tease out the impact thatkappa-opioids have on the descending pathway of opioid pain relief.
Three years ago, the Fields team showed that treating the vlPAG neurons of malerats with a mu opioid brought about pain relief, but that subsequently addingkappa-opioid into the RVM markedly decreased the mu opioid's analgesic effect.
In the current study, the team observed the opposite response. Treating thevlPAG neurons of female rats with a mu opioid brought on the expected painrelief, but subsequently adding kappa-opioid into the RVM increased the muopioid's analgesic effect.
"In males, kappa-opioid is somehow inhibiting the actions of mu opioid," saysFields.
One possible explanation, says Fields, is that the kappa receptors are actingon opposite types of neurons in males and females. In males, kappas may beinhibiting the so-called "off" nerve cells in the RVM that normally tell thespinal cord to shut off pain signals. In females, kappa-opioids actually excitethe off neurons, which would relieve pain.
In their study, the researchers also discovered that female rats receivedsignificantly more pain relief when mu opioid was injected into the vlPAG thanmale rats, a fact that was not attributable to body weight or diffusion of thedrug in the body.
This finding suggests, says Fields, that mu receptors in females also responddifferently to mu opioids than they do in males. The ultimate explanation forthe sexual dimorphism with respect to the mu and kappa-opioid receptors mayprove to be hormonal, says Fields.
But regardless of the explanation, he says, "People need to understand thatmale and female brains are different, period. And this fact has to be takeninto consideration when thinking about drug treatments, particularly drugs thatact 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 theDepartment 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 juiceof the opium poppy plant, and have been used for thousands of years to lessenpain and produce euphoria. They mimic naturally occurring forms of opioids --the neurotransmitters known as endorphins and enkephalins - which act in thebody in response to signals of pain, latching on to receptors on sensory nervecells that normally receive and transmit pain signals.
Many people develop tolerance to morphine, but at very different rates, someover weeks, some over months.
Cite This Page: