# New Modalities for the Treatment of Pain and Drug Abuse-Biochemical Core

> **NIH NIH P01** · UNIVERSITY OF ARIZONA · 2021 · $117,622

## Abstract

Project Summary Biochemical Core: 
Approximately 100 million American adults suffer from chronic pain with a societal cost of approximately 
$600 billion annually (Institute of Medicine 2011. Opioids effectively alleviate pain for many of these 
patients, but are limited by the development of adverse events (e.g. nausea, constipation, dependence) 
and decreased efficacy at tolerable doses over time. Despite a myriad of analgesic compounds on the 
market, nearly two-thirds of patients report inadequate pain relief while the risks associated with opioid 
addiction have increased. In the US, prescribed opioids have become the leading abused drugs and top 
reasons of injury death in the United States. While many studies in the last 15 years concerning opioid 
abuse have examined the idea that both injury and sustained opioid therapy can induce neuroplastic 
adaptations, no drug-development strategies have targeted such changes. These changes include 
endogenous increases in neurokinins, cholecystokinins and enzymes that rapidly degrade endogenous 
cannabinoids (i.e., FAAH, MAGL) after injury and in some cases after sustained opioid use. Antagonists 
to the neurokinin receptor-1 and to the CCK receptors-1&2 have been shown to be opioid sparing while 
decreasing many opioid induced side effects including rewarding behaviors in animals. In addition, many 
separate studies have identified analgesic efficacy of CB1 and CB2 compounds in animal models of 
chronic pain, yet no studies have investigated making a bifunctional compound of a CB2 agonist, CB1 
neutral antagonist/partial agonist or CB1/CB2 peripherally restricted agonists for chronic pain with 
reduced unwanted effects. Here we propose to test synthesized compounds with dual activity that 
includes opioid receptor agonism and either NK-1 (project A), CCK1/2 (project B) antagonism, or 
CB2-agonist/CB1-antagonist and peripherally restricted mixed CB1/2 agonists (project C) in order 
to increase analgesic efficacy while inhibiting unwanted side effects with improved drug stability 
& delivery. The Biochemical Core will provide the necessary screening of novel compounds 
synthesized by the Chemistry Core based on the knowledge and findings from each of the projects. Due 
to our years of experience in in vitro and in vivo studies, we will perform 6 aims to efficiently screen all 
compounds in a highly resourceful manner that will provide feedback to chemistry at all levels in order to 
develop the best analgesics for chronic pain. These include Aim 1, receptor binding for opioid, NK1, 
CCK, CB receptors, Aim 2, in vitro functional assays to determine agonist/antagonist activity as well as 
efficacy, Aim 3, in vivo assays for analgesic/anti-inflammatory activity, Aim 4, in vivo assay in a model of 
neuropathic pain, Aim 5, in vivo assays for unwanted side effects and Aim 6, In vivo pharmacokinetics. 
Once compounds have been shown to have efficacy in a model of neuropathic pain (aim 4) the 
compounds wi...

## Key facts

- **NIH application ID:** 10151588
- **Project number:** 5P01DA041307-05
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** TODD W VANDERAH
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $117,622
- **Award type:** 5
- **Project period:** 2017-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151588

## Citation

> US National Institutes of Health, RePORTER application 10151588, New Modalities for the Treatment of Pain and Drug Abuse-Biochemical Core (5P01DA041307-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10151588. Licensed CC0.

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