# Molecular genetic dissection of the spinal microcircuits of wind-up

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $430,770

## Abstract

Chronic pain is a debilitating condition that affects one in four Americans, and for which there is a pressing
need for safe, effective treatments. Chronic pain patients experience enhanced pain sensations and often
experience pain when innocuous stimuli are presented. However, the neural basis for this amplification is
poorly understood. Here, we propose to investigate the neural circuit basis for wind-up, a physiological type of
central hyperexcitability that may also contribute to persistent pain. The studies we are proposing will begin to
identify specific spinal circuitry involved in this amplification, and investigate whether these microcircuits are
altered in conditions of injury. This knowledge may elucidate new therapeutic targets for the treatment of pain,
which is the long-term goal of research of our program. In the first aim, we will use our novel
skin/nerve/DRG/spinal cord preparation combined with optogenetic approaches to examine the involvement of
select cell types in wind-up of cutaneous sensory inputs recorded in spinal projection neurons. These studies
will examine the roles of specific subsets of cutaneous sensory neurons in wind-up by optogenetic stimulation
of their cutaneous projections both in naïve mice and following nerve injury. We will also employ optogenetic
strategies to activate or inhibit specific subsets of genetically defined excitatory (neurotensin (Nt)-cre) and
inhibitory (nNos-creER) spinal interneurons to determine their roles in this process. In the second aim we will
examine potential neural network and/or synaptic mechanisms underlying the wind-up of sensory inputs. In
particular, we will test the role of persistent, reverberating currents in wind-up. In addition, investigate which
mediators cause the slow depolarizing current that is often observed with wind-up, and determine whether this
plays a contributing role. In the third aim, we will use a novel behavioral model of wind-up using temporal
summation of cutaneous sensory inputs. Specifically, we have developed a behavioral model of temporal
summation in mice using the same optogenetic stimulation that we previously used to induce wind-up in the
first aim. This will allow us, for the first time, to make a direct correlation between the physiological
phenomenon (wind-up) and a behavioral response to the perception of pain (temporal summation), using
place-aversion as a measure of nociception in mice. Completion of the studies proposed in this application will
provide new insights into spinal circuitry underlying the processing of sensory information, and how these
processes are altered following nerve injury. Importantly could provide potential targets for the development of
pharmaceutical therapies. These new therapies could provide for improved treatments for the alleviation of the
adverse symptoms of chronic neuropathic pain.

## Key facts

- **NIH application ID:** 10011884
- **Project number:** 5R01NS096705-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** H Richard Koerber
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $430,770
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10011884

## Citation

> US National Institutes of Health, RePORTER application 10011884, Molecular genetic dissection of the spinal microcircuits of wind-up (5R01NS096705-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10011884. Licensed CC0.

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