Our laboratory has focused on studying the influence of the brain stem on the sensation of pain. Pain is modulated at several anatomical sites, including the spinal cord and the rostral ventromedial medulla (RVM) in the brainstem. Physiological studies suggest that RVM neurons containing inhibitory neurotransmitters have axons that descend to the spinal cord, inhibiting spinal neurons that relay pain to the brain. However, in addition, there is evidence that excitatory neurons in the same region can facilitate pain.
The present focus of our work is the neuroanatomical circuitry underlying neuropathic pain. Pain can arise from damage (or the threat of damage) to the body. However, pain can also result from prior damage to a nerve; the resulting pain occurs without any threat of damage to the body and is referred to as neuropathic pain. Our laboratory recently discovered that over 20% of all neurons in the RVM are lost in response to damage to a peripheral nerve. However, this cell loss could be blocked completely by a drug (tauroursodeoxycholic acid, or TUDCA) that inhibits programmed cell death, or apoptosis.
Neuronal loss such as we observed in the RVM appears to be unprecedented: there are no direct synaptic connections between the RVM and the peripheral nerve that was lesioned, nor even between the peripheral nerve and neurons that project their axons to the RVM. Thus we currently are investigating the mechanism underlying this loss of RVM neurons, examining whether such “long-distance” cell loss might be occurring in response to other insults, trying to assess whether a specific population of RVM neurons (e.g. antinociceptive neurons) are lost after peripheral nerve damage, and attempting to determine whether TUDCA could be useful for preventing neuropathic pain in humans.
Our laboratory also collaborates with other researchers to examine the anatomical basis of sex differences in pain and analgesia. These studies have focused in particular on the interactions of sex steroids and opiate receptors.
In addition to our work on pain, we have also promoted methods for multi-color fluorescence microscopy as a research tool, and are presently developing optical microscopic methods related to confocal microscopy, digital deconvolution and optical super-resolution. The latter method allows the light microscope to attain resolution previously possible only with the electron microscope.
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
- Liu NJ, Murugaiyan V, Storman EM, Schnell SA, Kumar A, Wessendorf MW, Gintzler AR. Plasticity of signaling by spinal estrogen receptor α, κ-opioid receptor, and metabotropic glutamate receptors over the rat reproductive cycle regulates spinal endomorphin 2 antinociception: Relevance of endogenous-biased agonism. J Neurosci. 2017;37:11181-11191.
- Liu NJ, Murugaiyan V, Storman EM, Schnell SA, Wessendorf MW, Gintzler AR. Estrogens synthesized and acting within a spinal oligomer suppress spinal endomorphin 2 antinociception: ebb and flow over the rat reproductive cycle. Pain. 2017;158(10):1903-1914.
- Leong ML, Speltz R, Wessendorf M. Effects of chronic constriction injury and spared nerve injury, two models of neuropathic pain, on the numbers of neurons and glia in the rostral ventromedial medulla. Neurosci Lett. 2016;617:82-7.
- Leong ML. Gu M. Speltz-Paiz R. Stahura EI. Mottey N. Steer CJ. Wessendorf M. Neuronal loss in the rostral ventromedial medulla in a rat model of neuropathic pain. J Neurosci. 2011;31:17028-39.
- Liu NJ. Chakrabarti S. Schnell S. Wessendorf M. Gintzler AR. Spinal synthesis of estrogen and concomitant signaling by membrane estrogen receptors regulate spinal kappa- and mu-opioid receptor heterodimerization and female-specific spinal morphine antinociception. J Neurosci. 2011;31(33):11836-45.
- Arora D, Hearing M, Haluk DM, Mirkovic K, Fajardo-Serrano A, Wessendorf MW, Watanabe M, Luján R, Wickman K. Acute cocaine exposure weakens GABA(B) receptor-dependent G-protein-gated inwardly rectifying K+ signaling in dopamine neurons of the ventral tegmental area. J Neurosci. 2011;31(34):12251-7.
Former Graduate Students:
Ming Gu (Ph.D. 2007, Neuroscience, University of Minnesota).
Heather Leong (Ph.D. 2011, Neuroscience, University of Minnesota).
Sara Tallaksen-Greene (Ph.D.). Currently at the Department of Neurology, Univ. of Michigan, Ann Arbor
Wei Wu (Ph.D.). Currently at the Howard Hughes Research Institute, University of California-San Diego, La Jolla, CA