Reversal of pain by group II metabotropic glutamate receptors


Principal Investigator: Steve Davidson
Abstract: DESCRIPTION (provided by applicant): Inflammation or injury can sensitize nociceptive neurons and the resulting hyperexcitability is thought to mediate increased pain sensation. Although pain typically resolves with time, the mechanisms that promote the return to Dr. g are poorly understood. Dysfunction of such a mechanism could contribute to the persistence of chronic pain, while activation could provide relief from pain. The central hypothesis of this proposal is that peripheral group II metabotropic glutamate receptors (mGluRs) regulate the reversal of nociceptor sensitization and hyperalgesia. This hypothesis will be tested with a combination of anatomical, neurophysiological, and behavioral methods. Two subtypes of group II mGluRs exist, mGluR2 and mGluR3. The specific expression of each subtype within dorsal root ganglia (DRG) will be characterized. We will then determine whether mGluR2 or mGluR3 is necessary for the normal recovery from inflammatory and neuropathic pain using mGluR2 and mGluR3 knockout mice. We propose that group II mGluRs can reverse nociceptor sensitization. To test this, patch-clamp techniques will be used to measure neuronal excitability in sensitized DRG neurons. After pharmacological manipulation of group II mGluRs excitability will be reassessed. Membrane excitability is determined by current flux through ion channels, but it is not clear whether group II mGluRs regulate currents involved in sensitization. Two candidate currents, the tetrodotoxin- resistant Na+ and T-type Ca2+ current will be tested for their ability to be modulated by group II mGluRs in sensitized DRG neurons. We hypothesize that group II mGluRs are involved in the endogenous recovery from hyperalgesia. To test this, we will determine whether positive allosteric modulators of group II mGluRs accelerate the recovery from inflammatory hyperalgesia. Finally, we will determine whether group II mGluRs are capable of relieving ongoing neuropathic pain using an operant conditioning paradigm.
Funding Period: 2011-12-01 - 2014-11-30
more information: NIH RePORT

Detail Information

Research Grants30

  1. Varicella zoster virus-Induced Pain in a Rat Model of Post-Herpetic Neuralgia
    Paul R Kinchington; Fiscal Year: 2013
    ..The project may also identify new methods to alleviate PHN using gene therapy approaches. ..
  2. Endogenous Cannabinoids and Brain Function
    Aron H Lichtman; Fiscal Year: 2013
    ..Ultimately, the knowledge gained from this basic research will yield novel therapeutic targets that can be exploited with the pharmacological agents developed here. PROGRAM CHARACTERISTICS ..
  3. Sodium Channels in Spinal Cord Injury, Nerve Injury and Neuropathic Pain
    Stephen Waxman; Fiscal Year: 2013
    ..Our aim is to discover molecules that affect DRG neuron behavior, so that we can identify more effective treatments for neuropathic and inflammatory pain. ..