T-type Calcium Channel Inhibitors and Alpha Lipoic Acid as Novel Therapies for Treating Pain Post-surgery

Va Eastern Colorado Health Care System, Aurora CO

Investigators

Linked publications, trials & patents

Abstract

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 T-channels in central (spinal) sensitization of pain responses and its relationship with opioids 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 ? lipoic acid (ALA) underlies its potent peripheral anti-nociceptive effects. Our new preliminary and recently published data demonstrate that ALA displays excellent analgesia in a rat and mouse model of post-surgical pain resulting from paw skin incisions. 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 analgesic potency of ALA and its interactions with morphine using an established mouse model of postoperative incisional pain. In Aim 2, we will define the role of ALA in modulating synaptic transmission and neuronal excitability of nociceptive dorsal horn (DH) neurons using optogenetics. Here, we will use a novel transgenic mouse line in which CaV3.2 Cre mouse line will be crossed with channelrhodopsin-2 (Ch-R2) mouse line, an approach that will allow us to optogenetically enhance the activity of CaV3.2-containing nociceptive afferents. These studies will define the whole-cell neurophysiological effects of ALA in the major nociceptive pathway. We will also use confocal microscopy in order to study cellular and subcellular localization of CaV3.2 channels in DH and DRG neurons in mice with plantar surgical incision and after prolonged optogenetic stimulation that causes sensitization of pain responses. 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.