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Investigators Highlight Promising Preclinical Research Advances


doi: 10.1097/01.NT.0000335585.96525.4d
News From the Nih Pain Consortium
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Investigators discussed advanced in pain management — from cannabinoids and calsaicin to new data on factors affecting genetic susceptibility.

BETHESDA— “We are now regarding pain as a disease of the CNS. And almost every discipline has something to contribute to our understanding of pain at this point in time.”

So said Jennifer Haythornthwaite, PhD, a professor in the department of psychiatry and behavioral sciences at Johns Hopkins University, here at the third annual NIH-sponsored symposium on pain research. The interdisciplinary nature of the work and progress in translating basic science advances into clinical use was the theme for the all-day event held here on May 22.

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Several investigators focused on the analgesic effects of cannabinoids, compounds present in Cannabis sativa, the hemp plant from which marijuana is derived. A small clinical study published in the February 2008 issue of The Journal of Pain, the journal of the American Pain Society, showed that fibromyalgia patients treated with the synthetic cannabinoid nabilone had a significant reduction in pain and anxiety.

In rats, cannabinoid derivatives helped alleviate allodynia — a painful response to a usually non-painful stimulus — and decreased inflammation through desensitization of the neuronal TRPV1 channel, said Ken Hargreaves, DDS, PhD, professor and chair of the department of endodontics at the University of Texas Health Science Center.

Cannabinoids seem to activate different families of receptors to relieve pain, said Dr. Hargreaves, who is focusing on the peripheral nervous system in his preclinical research.

“I think his idea of using derivatives of cannabinoids is really novel,” because the derivatives may lack psychotropic side effects, said John Kusiak, PhD, program director for Molecular and Cellular Neurosciences at the National Institute of Dental and Craniofacial Research and moderator of a morning panel of presenters.

Dr. Kusiak, who was not involved in the research, said that for patients, “this may not be as far off as you might expect.” He cited by example the combination tetrahydrocannabinol and cannabidiol drug Sativex, which is approved in Canada. Used as an oral spray, it is in phase 3 clinical trials in the United States.

Preclinical work points to a synergy of opioids and cannabinoids and sphingolipids in the production of analgesia, said Sandra P. Welch, PhD, professor of pharmacology and toxicology at Virginia Commonwealth University. She noted that in mice, tetrahydrocannabinol (THC), the active ingredient in the Cannabis drug dronabinol (Marinol), releases natural endogenous opioids, leading to what she called the “M and M” hypothesis for pain relief: low-dose Marinol plus morphine.

“The effects of morphine are greatly enhanced by low-dose THC,” said Dr. Welch. A possible clinical application, she said, would be to use low-dose THC and a lower dose of an opioid for pain relief, in hopes of reducing opioid side effects such as constipation.



But while several investigators praised these developments with the new cannabis drugs as promising, one researcher urged caution. “Cannibinoids have been hyped; they are the ‘molecule on the block’ for neuroscientists,” said Wen G. Chen, PhD, program director for Sensory and Motor Disorders of Aging at the National Institute on Aging (NIA), who had no part in the research.

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At its basic level, pain consists of electrical signals in the nervous system, said Bruce P. Bean, PhD, professor of neurobiology at Harvard Medical School. He described preclinical results — reported with colleagues in the Oct. 4, 2007, issue of Nature—that selectively target pain fibers in regional anesthesia with the investigational drug QX-314, a permanently charged derivative of lidocaine that blocks the activity of sodium channels when applied internally.

“Could we use TRPV1 channels as a drug delivery system? Or could we use the TRPV1 channel as a way of getting QX-314 into the neuron?” Dr. Bean asked.

In work with rat dorsal root ganglia (DRG) neurons, Dr. Bean and colleagues activated TRPV1 by capsaicin, a metabolite produced by hot chili peppers, and then inhibited the sodium current via QX-314, thus inhibiting pain.

“Capsaicin is a painful molecule,” he noted. “That is an issue for clinical use.” Because of this, he said, he has been using lidocaine in place of capsaicin; co-applying lidocaine with QX-314 gives pain relief for 10 to12 hours, he explained.

Dr. Bean theorized that clinically this approach might be useful for local, regional anesthesia and during surgery for wound treatment as long-lasting anesthesia. Yet to be determined, he said, is how best to deliver this form of pain relief.

Commenting on Dr. Bean's work, Dr. Chen of the NIA said: “He's trying to move it into clinical settings; it's important to find the right combination and dosage. This could be a ‘combo’ pain drug.”

Added David Goldman, MD, chief of the Laboratory of Neurogenetics and senior investigator in the Human Neurogenetics Section at the National Institute on Alcohol Abuse and Alcoholism: Dr. Bean's strategy to deliver pain relief into the cell is “an amazing idea to achieve selectivity.”

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William Maixner, DDS, PhD, professor and director of the Center for Neurosensory Disorders at the University of North Carolina School of Dentistry, described research showing genetic variations in pain susceptibility. Dr. Maixner said that approximately 50 percent of pain sensitivity can be attributed to genetic factors. He cited polymorphisms in the catechol o-methyltransferase (COMT) gene (Val 158Met). The enzyme COMT degrades catecholamines, and in animal models heightened catecholamine levels increase pain sensitivity.

“These studies are at this point association studies,” said Dr. Maixner. He cited a poster presentation at the NIH meeting that showed that after a minor motor vehicle crash, people with the COMT met/met genotype had a lower cortisol response in a social stress test and increased pain symptoms in the emergency department.

Dr. Goldman, who has conducted research on neuropeptide Y (NPY), the most abundant peptide in the brain, said there are multilevel effects of functional alleles of NPY expression. “NPY expression affects pain, stress response, and emotion,” he said, noting that people with low levels of NPY tend to respond more to pain. Dr. Goldman said NPY expression tracks with haplotype ancestry, but, he cautioned, “The reality is that it [genetic expression] gets diluted as it goes to behavior.”

Dr. Goldman told Neurology Today that a clinical implication for treatment might be augmentation of NPY in a patient with low NPY expression, or manipulation of the stress axis therapeutically. “Eventually we'll have in our hands a panel of variances to use,” he predicted of genetic variations in human pain susceptibility.

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Several speakers highlighted animal research that model migraine in humans in an attempt to better understand the mechanisms that underlie migraine. Sumatriptan reverses hypersensitivity in the 5HT-1D receptor (the primary antinociceptive target of triptans) in a triptan-receptor knockout line of mice, said Andrew H. Ahn, MD, PhD, assistant professor in the department of neurology and anatomy at the University of California-San Francisco.

“Triptans activate multiple receptors at different sites,” said Dr. Ahn, adding, “Migraine is a multi-system disorder.” He said his research suggests that the amygdala plays a central role in pain processing.

“This work was really super, because it shows that sumatriptan appears to be acting not just in the spinal cord but also in the amygdala,” commented David Goldman, MD, chief of the Laboratory of Neurogenetics and senior investigator in the Human Neurogenetics Section at the National Institute on Alcohol Abuse and Alcoholism, who was not involved in Dr. Ahn's research.

Cortical spreading depression (CSD), a wave of depolarization that propagates across the cerebral cortical hemisphere and suppresses cortical activity during a migraine, can be studied in a mouse model with striking clinical implications, said Maiken Nedergaard, MD, PhD, a professor of neurosurgery at the University of Rochester Medical Center.

While the mechanism of CSD remains unknown, Dr. Nedergaard said the progress of CSD can be visualized on MRI as an astrocytic calcium wave, which causes not only pain but also an increased demand for oxygen. Although this wave is not hypoxia per se, there is a decrease in oxygen in brain tissues with CSD, so CSD can result in a transient severe hypoxic condition that could potentially cause brain damage. She noted that there are transient changes in dendrite morphology during CSD, such that dendrites lose their structure, especially their spine. While the dendritic spines come back in the same place, she noted, it takes about 10 to 15 minutes.

An audience member asked whether CSD could theoretically be treated with oxygen supplementation, and Dr. Nedergaard said yes.

“The areas of hypoxia would suggest that giving oxygen would be beneficial,” added Dr. Kusiak. Or, suggested Dr. Kusiak, another clinical approach might be to give a drug which elevates oxygen.

For more on cortical spreading depression and migraine, see this Neurology Today article on “Michael A. Moskowitz: Cortical Spreading Depression is Key to Migraine Genesis,” April 17, 2007.

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The NIH Pain Consortium is co-chaired by the directors of the National Institute of Dental and Craniofacial Research, NINDS, and the National Institute of Nursing Research. Co-sponsors of the pain symposium included the National Institute on Aging, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Institute on Drug Abuse. For more on the May 22 meeting and the consortium activities, visit

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• Skrabek RQ, Galimova L, Perry D, et al. Nabilone for the treatment of pain in fibromyalgia. J Pain 2008;9(2):164–173.
    • Binshtok AM, Bean BP, Woolf CJ. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 2007;449(7162):607–610.
      ©2008 American Academy of Neurology