# Injury-Induced Pain: Chemical Modulation of Nociceptors

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $358,203

## Abstract

PROJECT SUMMARY
The treatment of neuropathic pain (NP) remains unsatisfactory and presents a major global health and
economic burden to individuals and society. Unfortunately, currently available medications are not uniformly
effective and are associated with significant central nervous system (CNS) side effects that limit their clinical
utility. Translation from preclinical findings to a viable clinical therapy for NP has been fraught with
disappointments, possibly because animal studies have primarily relied on outcome measures such as reflex
responses that fail to mimic the chief symptom of spontaneous and ongoing pain in patients. Our recent
studies suggested that peripherally acting µ-opioid receptor (MO-R) agonists alleviate mechanical and heat
hypersensitivities in rodent models of NP. Here, our preliminary studies also indicate a role for peripheral
cannabinoid receptors (CB-R) in NP, and further suggest that both peripheral MO-R and CB-R are valuable
targets for alleviating ongoing pain after nerve injury. Based on these novel findings, we hypothesize that: 1)
Activation of CB1-R and MO-R in the peripheral nervous system (PNS) attenuates ongoing NP, and has no
significant adverse effects that would suggest CNS penetration, impaired G.I. motility, or undesirable immune
effects; 2) Subpopulations of DRG neurons, especially those that express CB1-R, MO-R, and TRPV1, develop
spontaneous activity after injury that can be inhibited by peripherally acting CB1-R and MO-R agonists; 3)
Activation of peripheral neuronal CB1-R and MO-R decreases nociceptive transmission in dorsal horn neurons;
4) CB1-R agonists enhance peripherally acting MO-R agonist-induced inhibition of NP-related behavior by
potentiating MO-R-mediated inhibition of DRG neurons. A broad range of strategies will be used to rigorously
test our hypotheses in three inter-related Aims. In Aim 1, the efficacy, receptor subtypes involved, and potential
adverse effects of systemic administration of the drugs will be studied. In Aim 2, we will use calcium imaging,
patch clamp recording in spinal cord slices, and in vivo dorsal horn recordings to determine the mechanisms by
which CB13 and DALDA inhibit ongoing NP in the PNS. In Aim 3, we will examine the functional interactions
between CB1-R and MO-R in PNS for NP inhibition. Our study involves comprehensive and innovative
approaches including: Operant behavioral tests to reveal the relief of ongoing and affective components of NP,
high-throughput Pirt-GCaMP6 calcium imaging of DRG neurons in vivo, peripherally restricted CB1-R and MO-
R conditional knockout (cKO) mice using a Cre/loxP system, neurophysiologic recordings in functionally
distinct subgroups of dorsal horn neurons (e.g., excitatory, GABAergic inhibitory) identified by fluorescence,
and multiplex cytokine ELISA. The results of these studies will provide new insights into the mechanisms that
underlie the peripheral pain-inhibitory effects of opioids and cannabinoids, and will c...

## Key facts

- **NIH application ID:** 9830078
- **Project number:** 5R01NS026363-29
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** SRINIVASA N. RAJA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $358,203
- **Award type:** 5
- **Project period:** 1989-04-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830078

## Citation

> US National Institutes of Health, RePORTER application 9830078, Injury-Induced Pain: Chemical Modulation of Nociceptors (5R01NS026363-29). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9830078. Licensed CC0.

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