# Endovanilloid-Mediated Modulation and its Role in Habituation and Sensitization

> **NIH NIH R01** · UNIVERSITY OF SOUTH DAKOTA · 2020 · $285,995

## Abstract

Chronic pain is a major health care burden in the US, affecting approximately 100 million people at an annual
cost of $635 billion. This proposal will examine modulation in pain signaling (nociception) as a form of learning
and memory. Acquisition of a nociceptive memory represents a form of sensitization-type learning involving
either an increased response to nociceptive stimuli (hyperalgesia) or having non-nociceptive stimuli elicit a
painful response (allodynia). Habituation, on the other hand, is a potential mechanism to erase a nociceptive
memory and may represent an unrecognized process contributing to forms of analgesic modulation such as
gate-control of pain or stress-induced analgesia. This approach has benefits not only in understanding how pain-
induced sensitization develops, but also in potentially using learning-based approaches to reduce pain, such as
using habituation to reduce activity in nociceptive circuits.
 We have identified a modulatory process, specifically endocannabinoids acting through Transient Receptor
Potential Vanilloid (TRPV) channels, that contributes to both pain-related sensitization and habituation of pain-
evoked behaviors. Endocannabinoids are lipid neurotransmitters that activate either metabotropic cannabinoid
receptors (CB1 and CB2) or TRPV channels (in which case endocannabinoids are sometimes referred to as
endovanilloids). While there is considerable interest in cannabinoid-based therapies, their effectiveness in
treating chronic pain is questionable. This is, in part, because endocannabinoids can exert both anti-nociceptive
and pro-nociceptive effects. Endocannabinoids can depress nociceptive synapses (an anti-nociceptive effect)
and we have evidence that this modulatory process contributes the ability of repetitive non-painful stimuli to
reduce responses to painful stimuli, a form of transfer of habituation. Endocannabinoids also mediate synaptic
disinhibition/potentiation of non-nociceptive synapses, a pro-nociceptive effect that may contribute to pain-
induced sensitization. In this study, we will examine the role of endocannabinoids and TRPV signaling during
nociception-related sensitization and habituation using Hirudo verbana (the medicinal leech). This approach
takes advantage of the well-characterized nervous system of Hirudo in which we have already identified distinct
synapses that undergo either endocannabinoid/TRPV-mediated depression or disinhibition/potentiation. An
additional advantage is that Hirudo lacks CB1 and CB2 receptors, so it is possible to isolate the role of
endocannabinoids acting via TRPV. In Aim 1, the cellular mechanisms mediating endocannabinoid/TRPV-
induced potentiation of non-nociceptive synapses will be examined as well as how this plasticity contributes to
sensitization to non-painful stimuli (allodynia). In Aim 2, the role of endocannabinoid/TRPV-mediated depression
of nociceptive synapses during habituation will be studied as well as whether this habituation can re...

## Key facts

- **NIH application ID:** 10003855
- **Project number:** 5R01NS092716-05
- **Recipient organization:** UNIVERSITY OF SOUTH DAKOTA
- **Principal Investigator:** Brian Donald Burrell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $285,995
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003855

## Citation

> US National Institutes of Health, RePORTER application 10003855, Endovanilloid-Mediated Modulation and its Role in Habituation and Sensitization (5R01NS092716-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10003855. Licensed CC0.

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