Saturday, November 23, 2024
11/23/2024
Pain-sensing sensory neurons of the dorsal root ganglion (DRG) and dorsal horn (DH) can become sensitized (hyperexcitable) in response to surgically induced peripheral 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. The important role of voltage-gated calcium channels (VGCCs) in pain processing has been recognized for a while since calcium (Ca2+) is the major trigger for the release of synaptic vesicles from neuronal presynaptic terminals in response to noxious stimulation. An increase of intracellular Ca2+ in pain sensing neurons (nociceptors) can also influence the excitability of these cells. We established that CaV3.2 (T-type) calcium-channels make a previously unrecognized contribution to sensitization of pain responses by enhancing excitability of peripheral nociceptors. We also showed that the blockade of CaV3.2 currents in nociceptive DRG neurons by 5-reduced neuroactive steroids (NASs) underlies their potent peripheral anti-nociceptive effects in a clinically relevant rodent model of perioperative pain model of plantar skin incision. In addition, we have shown that NASs that inhibit CaV3.2 channels are effective in alleviating mechanical hyperalgesia post-surgery when administered preemptively whereas morphine provides dose-dependent pain relief only when administered once the pain had developed. However, limited aqueous solubility and potent hypnotic/sedative effects linked to their direct or indirect (via metabolic pathways) effect on GABAA receptors may hinder future development of NASs for novel pain therapies. Hence, we will follow up on our exciting findings that inhibition of neuronal CaV3.2 in pain pathways underlies effective post-operative analgesia with novel analogues of NASs that have more favorable pharmacokinetic and pharmacodynamic properties, as well as better solubility. The Specific Aims are: Aim #1: To develop NAS CaV3.2 inhibitor analogues with diminished potential for conversion to GABAA positive allosteric modulators and test hypothesis that their analgesia is mediated via inhibition of CaV3.2 channels. Aim #2: To study analgesic potency of novel analogues of NASs and their interactions with morphine using a rodent model of postoperative incisional pain and chronic constrictive injury (CCI) of sciatic nerve. Aim #3: To define the role of novel NASs in modulating synaptic transmission and neuronal excitability of nociceptive dorsal horn (DH) neurons using optogenetics. The proposed work is innovative and medically significant because we anticipate that our studies will identify novel therapies for perioperative pain that may greatly decrease the need for narcotics and potential for drug abuse.
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