# Endogenous cannabinoid signaling in the development of chronic neuropathic pain

> **NIH VA I01** · CLEMENT J. ZABLOCKI VA MEDICAL CENTER · 2021 · —

## Abstract

Neuropathic pain is a common problem among Veterans that substantially impedes their efforts to rehabilitate
function following injury. Current treatments are inadequate, but our recent observations show that cannabinoids
hold promise for new therapeutic approaches. Systemic administration of cannabinergic drugs has limited
analgesic utility due to diverse side effects, such as unwanted psychoactive changes. However, there is
growing recognition of the participation of endocannabinoids (ECs), the endogenous agonists of cannabinoid
receptors, in driving CNS pain regulation through descending inhibition of sensory pathways, indicating a
possible avenue for therapy. The dorsal periaqueductal gray (dPAG) is a key midbrain center for EC-driven
antinociception mediated by descending sensory inhibition that is coordinated with enhanced autonomic
function through sympathoexcitation. Our promising preliminary data in rats show that maladaptations of EC
signaling in the dPAG, including upregulation of the catabolic enzyme fatty acid amide hydrolase (FAAH) and
reduced levels of the EC N-arachidonoylethanolamine (AEA), are associated with the development of chronic
pain and autonomic dysfunction after nerve injury. These findings suggest that individuals who develop chronic
neuropathic pain would benefit from increased EC signaling, particularly in the dPAG. We propose to test the
hypothesis that dysregulation of endogenous cannabinoid signaling contributes to the transition from
acute to chronic neuropathic pain. The first objective of the proposed studies is to determine the therapeutic
potential of enhanced EC signaling in the treatment of chronic neuropathic pain and, critically, in the prevention
of acute pain progressing to chronic pain. To achieve this, we will test whether attenuation of hyperalgesia can
be achieved in vivo with FAAH inhibition (Specific Aim 1), positive allosteric modulation or a combination of
both (Specific Aim 2), for effective and safe prevention or treatment of chronic neuropathic pain. These aims
will evaluate the dPAG as a site of action for enhanced EC signaling, which is a vital step towards future
development of targeted delivery of therapeutic molecules for increased specificity and decreased adverse
consequences. The VA is committed to pursuing a better understanding of causes and potential treatments of
chronic pain in women veterans as there is no doubt that female sex heavily predisposes a subject to chronic
pain. There is also convincing evidence that endogenous analgesic processes are more cannabinoid
dependent in females than in males. Specific Aim 3 will address the significant health concern of the gender
gap in the diagnosis and treatment of chronic pain by evaluating mechanisms contributing to sex differences in
the development of chronic neuropathic pain and its treatment through enhanced CB1R signaling.

## Key facts

- **NIH application ID:** 10091983
- **Project number:** 5I01RX002747-03
- **Recipient organization:** CLEMENT J. ZABLOCKI VA MEDICAL CENTER
- **Principal Investigator:** CARON DEAN-BERNHOFT
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10091983

## Citation

> US National Institutes of Health, RePORTER application 10091983, Endogenous cannabinoid signaling in the development of chronic neuropathic pain (5I01RX002747-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10091983. Licensed CC0.

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