Chronic pain is affecting over 100 millions of U.S. adults with its debilitating medical problems, inadequate treatment, and severe economic burdens (over $600 billion). This is due to limited efficacy or intolerable side effects of available analgesic options. In order to better serve chronic pain patients, it is better to have clearer understanding of how chronic pain is generated. We don?t know exactly how innocuous stimuli (i.e. normal input to A?-fiber activation) become painful, leading to chronic pain after injury. And it remains unclear how the encoding of mechanosensory information to brain area is conveyed after it is sensitized at the level of primary sensory neuron and spinal cord. Although the mechanisms of hyperexcitability of individual DRG neurons have been extensively studied, how DRG neurons function at a populational level as an ensemble under physiological and pathological conditions is unclear due to the lack of suitable tools and techniques. Here, we developed an imaging technique that allowed us to simultaneously monitor the activation of >1,600 neurons/DRG in response to mechanical stimulation applied to the skin in live mice. And we now acquired and obtained mouse genetic tools that allow visualization of all four major Low Threshold Mechanoreceptor (LTMR) subtypes; A?, SA-LTMRs, A?, RA-LTMRs, A?-LTMRs, and C-LTMRs. Specific labeling of distinct sensory neuron subtypes provide an unprecedented opportunity to determine whether the activity of each subtype is altered during chronic pain after nerve injury. Using this powerful techniques and tools, we discovered a striking neuronal coupling phenomenon as a novel pain mechanism that adjacent neurons activate together following inflammation or nerve injury, although this rarely happens in nave animals. This is the first demonstration that coupling phenomenon of primary sensory neurons after nerve injury contributes to new mechanisms underlying chronic pain conditions. This coupling activation occurs among various sizes of neurons including small-diameter nociceptors and large-diameter low-threshold mechanoreceptors. Combining the imaging technique with pharmacological and genetic approaches, we found that the coupling is, in part, mediated by an injury-induced upregulation of gap junction in satellite glial cells surrounding DRG neurons. Blocking gap junctions significantly attenuated neuronal coupling in the DRG and also reduced mechanical hyperalgesia. Therefore, neuronal coupling represents a new form of neuronal plasticity in the DRG and by ?hijacking? neighboring neurons through gap junction it contributes to pain hypersensitivity. Our studies suggest a new strategy to alleviate neuropathic pain by inhibiting gap junction connection between DRG neurons.

Public Health Relevance

Chronic pain resulting from inflammation and nerve injury has a large impact on a patient?s quality of life and approximately over 100 million U.S. adults are suffered from chronic pain and its severe economic burdens (over $600 billion per year). Improved, mechanism-based therapies are therefore needed to reduce the enormous toll of chronic pain on individuals and public health and we still don?t know how primary sensory neurons function at a population level as an ensemble under physiological and pathological conditions due to the lack of suitable tool and technique. Here, we developed an imaging technique that allowed us to simultaneously monitor the activation of over 1,600 neurons per primary sensory neurons in response to mechanical stimulation applied to the skin in live mice in order to develop mechanism-based therapies and therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE026677-02
Application #
9393998
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Vallejo, Yolanda F
Project Start
2017-01-01
Project End
2021-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Med Br Galveston
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Kim, Yu Shin; Anderson, Michael; Park, Kyoungsook et al. (2016) Coupled Activation of Primary Sensory Neurons Contributes to Chronic Pain. Neuron 91:1085-1096