Olivera Nesic, Ph.D., Assistant Professor
Our research group is interested in better understanding chronic neuropathic pain (CNP), which is developed by approximately 70% of spinal cord injury ( SCI) patients in the weeks and months after trauma. As with other sufferers from neuropathic pain, only a small percentage of CNP patients find relief with currently available drugs. Our central hypothesis is that a severe and chronic disturbance in water/ion homeostasis in the injured spinal cord results in hyperexcitability of neurons in the pain pathways, and consequently results in the development of CNP. Therefore, our research focuses on the water channel proteins (aquaporins) and their possible link to CNP after SCI.
Aquaporin 4 (AQP4) is the most abundantly expressed aquaporin in the central nervous system ( CNS). Astrocytes expressing Aquaporin 4 mediate water transport between blood, cerebrospinal fluid and CNS parenchyma. Alterations in AQP4 expression levels are always associated with pathological changes in CNS, and nearly always contribute to edema formation.After SCI, activated astrocytes express significantly higher levels of AQP4. We believethat excessive up-regulation of AQP4 in chronically injured spinal cords induces water accumulation in astrocytes, and therefore their swelling. Numerous processes are triggered in swollen astrocytes: ion disturbance (e.g. K + buffering); amino acid release, Ca 2+ signaling and neurotransmission changes. Additionally, glial swelling reduces the extracellular space, which then results in an accumulation of ions and other neuroactive substances in the CNS parenchyma. All these processes are likely to increase neuronal excitability and consequently induce pain development: The involvement of AQP4 and astrocytic swelling in the pathogenesis of neuropathic pain conditions has not been previously studied.
Aquaporin 1 (AQP1) is another water channel expressed in the CNS. Interestingly, after SCI, AQP1 is upregulated primarily in pain fibers transmitting pain from the periphery, which suggests a previously uncharacterized link between water/ion homeostasis and pathological pain processing.
We anticipate that our studies should lay the foundation for new therapeutic approach targeting osmoregulation of astrocytes and neurons to attenuate neuropathic pain after SCI.
