T-type calcium channel inhibitors and alpha lipoic acid as novel therapies for treating pain post-surgery

点击翻译按钮获取中文摘要

Pain-sensing sensory neurons of the dorsal root ganglion (DRG) and dorsal horn (DH) can become sensitized (hyperexcitable) in response to the tissue injury. Because of insufficient knowledge about the mechanisms for this sensitization, current treatment for postoperative pain has been limited to somewhat non-specific systemic drugs (opioids) having significant side effects or potential for abuse. Recent studies in our laboratory have established that CaV3.2 (T-type) calcium-channels voltage-gated calcium channels make a previously unrecognized contribution to sensitization of pain responses by enhancing excitability of peripheral nociceptors in the setting of surgically induced tissue injury. Despite the established role of CaV3.2 channels in the pathogenesis of peripheral sensitization of pain responses, the role of multiple isoforms of T-channels (CaV3.1, CaV3.2 and CaV3.3) in central (spinal) sensitization of pain responses is not well studied. We previously showed that the blockade of CaV3.2 currents in nociceptive DRG neurons by an endogenous compound and dietary supplement a lipoic acid (ALA) underlies its potent peripheral anti-nociceptive effects. Our new data demonstrate that ALA displays excellent analgesia in a rat model of post-surgical pain resulting from paw skin incisions, and that CaV3.1 isoform of T-channels is also important for the development of hyperalgesia in a mouse model of paw incision. Thus, we propose that ALA may represent a safer class of analgesics having desirable analgesic properties in post-operative period by targeting T-channels in pain pathway, as well as being able to reduce the risk for the opioid addiction. In Aim 1, we will study the roles of CaV3.1 and CaV3.2 channels in ALA-induced analgesia using a clinically relevant rodent model of skin and deep tissue incision. In Aim 2, we will define the role of ALA in modulating synaptic transmission and neuronal excitability of nociceptive DH neurons. In this Aim, we will also test the hypothesis that ALA may reverse hyperexcitability in the identified nociceptive DH neurons in the rats following plantar skin incision. These studies will define the whole-cell neurophysiological effects of ALA in the major nociceptive pathway. Finally, we will also use electron microscopy to study cellular and subcellular localization of CaV3.1 and CaV3.2 channels in nociceptive DH neurons. The proposed work is innovative and medically significant because we anticipate that our preclinical studies will identify novel therapies for perioperative pain that may greatly decrease the need for narcotics and potential for drug abuse.