TWO TYPES OF ROS ARE DIFFERENTIALLY INVOLVED IN SPINAL SYNAPTIC PLASTICITY AND MECHANICAL HYPERSENSITIVITY IN NEUROPATHIC PAIN

Central sensitization, characterized by an increase in dorsal horn synaptic efficacy, is believed to underlie the chronic nature of neuropathic pain. It has been shown that pain-relaying synapses in the dorsal horn express two forms of long term changes in excitability––long term potentiation (LTP) and long term depression (LTD)––which contribute towards increased pain signaling to higher brain regions. Molecular mechanisms involved in the induction and maintenance of spinal LTP and LTD are still unclear. This study investigates the type of synaptic plasticity expressed by two major types of pain-relaying neurons in the dorsal horn, excitatory spinothalamic tract neurons (STTn) and inhibitory gamma-amino-butyric acid interneurons (GABAn). In addition, reactive oxygen species (ROS) have been recently shown to play an indispensable role in pain related synaptic plasticity. Therefore, this study further investigates the role of ROS in STTn and GABAn synaptic plasticity. First, synaptic plasticity in STTn and GABAn was induced using different conditioned stimulation (CS) paradigms (high frequency and low frequency). Second, calcium influx following CS was imaged in STTn and GABAn. Third, the role of two types of ROS (superoxide and hydroxyl radicals) in pain behavior as well as in CS-induced STTn and GABAn synaptic plasticity was investigated. The role of superoxide and hydroxyl radicals was also investigated in spinal nerve ligation (SNL)-induced synaptic plasticity. Results indicate that synaptic plasticity in the dorsal horn is cell-type specific; STTn express LTP whereas GABAn express LTD consistently independent of CS frequency. Calcium influx was found to be similar in dynamics during the induction of both STTn-LTP and GABAn-LTD. In addition, it was found that superoxide and hydroxyl radicals induce different levels of hyperalgesia and play a differential role in CS-induced STTn-LTP and GABAn-LTD as well as in SNL-induced changes in STTn and GABAn cellular excitability. Results hold key findings that might be helpful in better directing potential treatment methods for neuropathic pain.