# Novel neurosteroid anesthetics and perioperative analgesia

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $342,340

## Abstract

Project Summary
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. Recent
studies in our laboratory have established that CaV3.2 (T-type) calcium-channels and CaV2.3 (R-type) voltage-
gated calcium channels make a previously unrecognized contribution to sensitization of pain responses by
enhancing excitability of peripheral nociceptors and controlling excitatory synaptic transmission in the DH of
the spinal cord. We previously showed that the blockade of CaV3.2 currents in nociceptive DRG neurons by
5β-reduced neuroactive steroids underlies their potent peripheral anti-nociceptive effects. Our new data
demonstrate that one such steroid, 3β-OH [(3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile], in addition to
hypnotic properties, also displays excellent spinally-mediated analgesia. We also found that 3β-OH inhibits
recombinant CaV2.3 currents. This finding has led us to hypothesize that: inhibition of neuronal CaV3.2 and
CaV2.3 currents in pain pathways with the novel anesthetic 3β-OH and related neuroactive steroids underlies
effective analgesia. In Aim 1, we will study analgesic potency of neuroactive steroids using a clinically relevant
rodent model of skin and deep tissue incision. In Aim 2, we will define the role of neuroactive steroids in
modulating synaptic transmission and neuronal excitability of nociceptive DH neurons. These studies will
define the whole-cell neurophysiological effects of test compounds in the major nociceptive pathway. We will
also use electron microscopy to study cellular and subcellular localization of CaV2.3 and CaV3.2 channels in
nociceptive DH neurons. In Aim 3, we will study mechanisms and structure-activity relationships of steroid
inhibition of recombinant and native CaV2.3 currents in the nociceptive DRG neurons. The main goal of this
aim is to expand the limited information currently available with the expectation that the information obtained
will be important for the design of more potent and selective inhibitors of CaV2.3 channels that can be
important in developing novel and safer anesthetics and analgesics. 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.β

## Key facts

- **NIH application ID:** 9926278
- **Project number:** 5R01GM123746-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Vesna Jevtovic-Todorovic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $342,340
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926278

## Citation

> US National Institutes of Health, RePORTER application 9926278, Novel neurosteroid anesthetics and perioperative analgesia (5R01GM123746-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9926278. Licensed CC0.

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