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Stem cells found to relieve tough chronic pain in mouse study

May 25, 2012
Courtesy of University of California - San Francisco
and World Science staff

An em­bry­on­ic stem-cell trans­plant might quell the hardest-to-treat kinds of pain, sci­en­tists re­port, though such a med­i­cal ad­vance could al­so raise acute eth­i­cal dilem­mas.

Univers­ity of Cal­i­for­nia-San Fran­cis­co re­search­ers, work­ing with mice, fo­cused on treat­ing chron­ic pain that arises from nerve in­ju­ry—so-called neu­ro­path­ic pain. They took im­ma­ture nerve cells from em­bryos and used them to make up for a loss of func­tion of spe­cif­ic nerve cells in the spi­nal cord that nor­mally damp­en pain sig­nals.

Some of the trans­planted cells sur­vived and be­came func­tioning nerve cells in the spi­nal cord’s cir­cuit­ry, the re­search­ers found; signs of pain hy­per­sen­si­v­ity linked to nerve in­ju­ry al­most van­ished. This oc­curred with­out ev­i­dence of move­ment dis­tur­bances that are com­mon side ef­fects of the lead­ing drug treat­ment, added the in­ves­ti­ga­tors, re­porting their find­ings in the March 24 is­sue of the jour­nal Neu­ron.

“We are work­ing to­ward the pos­si­bil­ity of po­ten­tial treat­ments that might elim­i­nate the source of neu­ro­path­ic pain, and that may be much more ef­fec­tive than drugs that aim only to treat symp­to­mat­ic­ally the pain,” said the sen­ior au­thor of the stu­dy, Al­lan Bas­baum, chair of the school’s anat­o­my de­part­ment.

The medical use of im­ma­ture cells, or stem cells, from em­bryos has caused an out­cry among re­li­gious or­gan­iz­a­tions and oth­er groups due to the fact that the em­bryos usu­ally must be killed. A med­i­cal ad­vance that pits de­fense­less em­bryos against the des­per­ate needs of pain suf­fer­ers could cre­ate a di­lem­ma for so­ci­e­ty. In a some med­i­cal re­search areas, sci­en­tists have even­tu­ally found ways to ob­tain needed stem cells in ways that don’t in­volve harm­ing em­bryos.

Chron­ic pain, and an in­creas­ingly wide­spread de­pend­en­cy on drugs with harm­ful side ef­fects to han­dle it, is anoth­er is­sue af­flict­ing Amer­i­can so­ci­e­ty. Al­though pain and hy­per­sen­si­tiv­ity af­ter in­ju­ry usu­ally dis­si­pate, they some­times out­last the in­ju­ry, and be­come chron­ic pain. Many types of chron­ic pain are trig­gered by stim­u­li that are bas­ic­ally harm­less — such as light tou­ch — but that are per­ceived as pain­ful, said Bas­baum. This con­di­tion can be de­bil­i­tat­ing. Many peo­ple suf­fer from chron­ic neu­ro­path­ic pain af­ter a bout of shin­gles, years or dec­ades af­ter the vi­rus that causes chick­en pox has been van­quished. 

Chron­ic pain is not the same as or­di­nary pain pro­longed, Bas­baum said. Its vic­tims of­ten get lit­tle re­lief, even from pow­er­ful nar­cot­ic painkillers. Gabapentin, an an­ti­con­vul­sant first used to treat ep­i­lep­sy, now is con­sid­ered the most ef­fec­tive treat­ment for neu­ro­path­ic pain, but it only works for roughly 30 per­cent of pa­tients—and even for them pro­vides only about 30 per­cent re­lief, he said.

Neu­ro­path­ic pain seems to oc­cur be­cause af­ter an in­ju­ry nerve cells can die, or brain and spi­nal cir­cuit­ry may change, he added. These changes con­trib­ute to a state of hyper-excitabil­ity, en­hanc­ing the trans­mis­sion of pain mes­sages to the brain.

The dam­age may af­fect “in­hibito­ry” nerve cells in the spi­nal cord that nor­mally re­lease a mol­e­cule that in­hibits pain, called GABA, biol­og­ists say. A loss of GABA in­hi­bi­tion al­so is im­pli­cat­ed in ep­i­lep­sy and may play a role in Parkin­son’s dis­ease. Gaba­pentin helps to com­pen­sate for the loss of in­hi­bi­tion that GABA nor­mally would pro­vide, though it does not act like GABA, Bas­baum said.

Before his new research, some col­leagues had al­ready been ex­pe­ri­ment­ing with trans­plan­ti­ng im­ma­ture cells that make GABA, us­ing these to bol­ster in­hib­i­to­ry sig­nals in mouse mod­els to pre­vent seizures and com­bat a Parkin­son’s-like dis­ease. But in those ex­pe­ri­ments the cells — which orig­i­nate in a re­gion of the brain called the me­di­al gan­gli­on­ic em­i­nence — were merely trans­planted from one part of the brain to anoth­er.

Up­on hear­ing of the work, Bas­baum be­came in­ter­est­ed in trans­plan­ti­ng the same cells in­to the spi­nal cord as a po­ten­tial treat­ment for the loss of GABA-driven in­hi­bi­tion in neu­ro­path­ic pain. Suc­cess was by no means as­sured, as cells nor­mally don’t sur­vive out­side their nat­u­ral en­vi­ron­ments with­in such a com­plex or­ganism. What helped was that anoth­er co-au­thor of the Neu­ron stu­dy, John Ruben­stein, had been iden­ti­fy­ing mol­e­cules that can be ma­ni­pu­lated to lead an em­bry­on­ic stem cell to go through de­vel­op­mental stages that cause it to ac­quire the prop­er­ties of GABA neu­rons from the me­di­al gan­gli­on­ic em­i­nence.

“This re­search is at a very early stage, and we’re a long way from think­ing about it in hu­man tri­als, but we do have a meth­od of mak­ing cells that are like these in­hib­i­to­ry” cells, said study co-au­thor Ar­nold Krieg­stein, who di­rects the uni­vers­ity’s Broad Cen­ter of Re­genera­t­ion Med­i­cine and Stem Cell Re­search. “Un­like drugs, the trans­planted cells can have very fo­cused ef­fects, de­pend­ing on where they are trans­planted.”

* * *

An embryonic stem-cell transplant might quell the hardest-to-treat kinds of pain, scientists report, though such a medical advance could also raise acute ethical dilemmas. University of California San Francisco researchers, working with mice, focused on treating chronic pain that arises from nerve injury—so-called neuropathic pain. They transplanted immature embryonic nerve cells that arise in the brain during development and used them to make up for a loss of function of specific nerve cells in the spinal cord that normally dampen pain signals. Some of the transplanted cells survived and became functioning nerve cells in the spinal cord’s circuitry, the researchers found; signs of pain hypersensitivity linked to nerve injury almost vanished. This occurred without evidence of movement disturbances that are common side effects of the leading drug treatment, added the investigators, reporting their findings in the March 24 issue of the journal Neuron. “We are working toward the possibility of potential treatments that might eliminate the source of neuropathic pain, and that may be much more effective than drugs that aim only to treat symptomatically the pain,” said the senior author of the study, Allan Basbaum, chair of the school’s anatomy department. The use of immature cells, or stem cells, from embryos in medicine has caused an outcry among religious organizations and other groups due to the fact that the embryos usually must be killed. A medical advance that pits defenseless embryos against the desperate needs of pain sufferers could create a dilemma for society. In a number of medical research fields, though, scientists have eventually found ways to replace stem cells from embryos with stem cells from other sources. Chronic pain, and an increasingly widespread dependency on drugs with harmful side effects to handle it, is another issue afflicting American society. Although pain and hypersensitivity after injury usually dissipate, they sometimes outlast the injury, and become chronic pain. Many types of chronic pain are induced by stimuli that are essentially harmless — such as light touch — but that are perceived as painful, said Basbaum. This condition can be debilitating. Many people suffer from chronic neuropathic pain after a bout of shingles, years or decades after the virus that causes chicken pox has been vanquished. Chronic pain is not the same as ordinary pain prolonged, Basbaum said. Its victims often get little relief, even from powerful narcotic painkillers. Gabapentin, an anticonvulsant first used to treat epilepsy, now is considered the most effective treatment for neuropathic pain, but it only works for roughly 30 percent of patients—and even for them provides only about 30 percent relief, he said. Neuropathic appears to occur because after an injury nerve cells can die, or brain and spinal circuitry may change, he added. These changes contribute to a state of hyper-excitability, enhancing the transmission of pain messages to the brain. The damage may affect “inhibitory” nerve cells in the spinal cord that normally release a molecule that inhibits pain, called GABA. A loss of GABA inhibition also is implicated in epilepsy and may play a role in Parkinson’s disease. Gabapentin helps to compensate for the loss of inhibition that GABA normally would provide, though it does not act like GABA, he said. Colleagues of Basbaum had already been experimenting with transplanting immature neurons that make GABA, using the transplanted neurons to bolster inhibitory signals in mouse models to prevent seizures and combat a Parkinson’s-like disease. But in those experiments the cells — which originate in a region of the brain called the medial ganglionic eminence — were merely transplanted from one part of the brain to another. Upon hearing of the research, Basbaum became interested in transplanting the same cells into the spinal cord as a potential treatment for the loss of GABA-driven inhibition in neuropathic pain. Success was by no means assured, as cells normally don’t survive outside their natural environments within such a complex organism. What helped was that another co-author of the Neuron study, John Rubenstein, had been identifying molecules that can be manipulated to lead an embryonic stem cell to go through developmental stages that cause it to acquire the properties of GABA neurons from the medial ganglionic eminence. “This research is at a very early stage, and we’re a long way from thinking about it in human trials, but we do have a method of making cells that are like these inhibitory neurons, starting with human embryonic stem cells,” said study co-author Arnold Kriegstein, who directs the university’s Broad Center of Regeneration Medicine and Stem Cell Research. “Unlike drugs, the transplanted cells can have very focused effects, depending on where they are transplanted.”