# Novel neurosteroid anesthetics and perioperative analgesia

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $333,317

## Abstract

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.

## Key facts

- **NIH application ID:** 10979912
- **Project number:** 2R01GM123746-05A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Vesna Jevtovic-Todorovic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $333,317
- **Award type:** 2
- **Project period:** 2017-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979912

## Citation

> US National Institutes of Health, RePORTER application 10979912, Novel neurosteroid anesthetics and perioperative analgesia (2R01GM123746-05A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10979912. Licensed CC0.

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