Cell therapy may ease chronic pain

A new study has described how a cell therapy might one day be used not only to quell some common types of persistent and difficult-to-treat pain, but also to cure the conditions that give rise to them. UCSF scientists, working with mice, focused on treating chronic pain that arises from nerve injury -- so-called neuropathic pain. In their study, the scientists 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 neurons in the spinal cord that normally dampen pain signals. A small fraction of the transplanted cells survived and matured into functioning neurons. The cells integrated into the nerve circuitry of the spinal cord, forming synapses and signaling pathways with neighbouring neurons. As a result, pain hypersensitivity associated with nerve injury was almost completely eliminated, the researchers found, without evidence of movement disturbances that are common side effects of the currently favoured drug treatment. “Now 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 that results from chronic, painful conditions,” said the senior author of the study, Allan Basbaum, PhD, chair of the Department of Anatomy at UCSF. Those who suffer from chronic pain often get little relief, even from powerful narcotic painkillers, according to Basbaum. Gabapentin, an anticonvulsant first used to treat epilepsy, now is regarded as the most effective treatment for neuropathic pain. However, it is effective for only roughly 30 percent of patients, and even in those people it only provides about 30 percent relief of the pain, he said. The explanation for neuropathic pain, research showed, is that following injury neurons may be lost, or central nervous system circuitry may change, in ways that are maladaptive, compromising signals that normally help dampen pain. These changes contribute to a state of hyper-excitability, enhancing the transmission of pain messages to the brain and causing normally innocuous stimuli to become painful. The inhibitory neurons that are damaged in the spinal cord to cause pain hypersensitivity release a molecule that normally transmits inhibitory signals — the neurotransmitter GABA. A loss of GABA inhibition also is implicated in epilepsy and may play a role in Parkinson``s disease. Gabapentin does not mimic GABA, but it helps to compensate for the loss of inhibition that GABA normally would provide. Basbaum``s UCSF colleagues, including study co-authors Arturo Alvarez-Buylla, PhD, and Arnold Kriegstein, MD, PhD, along with Scott Baraban, PhD, had already been experimenting with transplanting immature neurons that make GABA, using the transplanted neurons to bolster inhibitory signals in mouse models to prevent epileptic seizures and to combat a Parkinson``s-like disease. However, in those experiments the cells — which originate in a region of the forebrain known as the medial ganglionic eminence — were transplanted within the brain itself, which is their normal home. Upon hearing about 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 do not survive outside their natural environments within such a complex organism. Another co-author of the Neuron study, UCSF researcher John Rubenstein, PhD, has made major progress in 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 that derive from the medial ganglionic eminence. According to Kriegstein, who directs the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, “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.” As a step toward eventual therapies, the UCSF team plans to graft fetal human cells from the medial ganglionic eminence, or cells derived from human embryonic stem cells, into a rodent model of neuropathic pain, to see if the human cells also will alleviate neuropathic chronic pain. The study was recently published in Neuron.