Summary: Transcriptional regulators related to the Brinker system control injury-induced increases in pain sensitivity and may provide new targets for therapies to treat chronic pain.
Source: University of New England
Chronic pain affects millions worldwide and remains a major clinical challenge. Better understanding of the cellular and molecular mechanisms that sustain pain after injury is essential to develop improved treatments.
A new study from the Ganter Lab, published in the journal Molecular Pain, advances understanding of how transcriptional regulation inside sensory neurons contributes to prolonged pain sensitivity following injury. Funded by the National Institutes of Health, the research was led by Geoffrey Ganter, Ph.D., professor of Biology, with contributions from lab members Aidan McParland, Julie Moulton, Courtney Brann, Yvonne Otis and Christine Hale.
After tissue damage, sensory neurons called nociceptors lower their threshold for activation and produce stronger pain signals — a protective response known as nociceptive sensitization. Normally this heightened sensitivity helps healing and then subsides, but when regulatory processes fail, sensitization can persist and contribute to chronic pain states. The Ganter Lab used Drosophila melanogaster (fruit fly) as a model system to dissect the molecular events that switch nociceptors between normal and sensitized states.
The investigators focused on the Bone Morphogenetic Protein (BMP) signaling pathway and its nuclear effectors, which act downstream of previously implicated Hedgehog signaling in injury responses. Specifically, the team examined two nuclear transcriptional regulators: Brinker (Brk), a repressor, and Schnurri (Shn), a transcriptional activator. Using RNA interference to selectively reduce expression of these factors in nociceptors, the researchers tested how each component influences baseline sensitivity and the development of injury-induced hypersensitivity.
Loss of Brinker in nociceptors produced a striking result: animals showed hypersensitivity even without an injury, indicating that Brinker normally keeps the expression of pain-promoting genes in check. In contrast, reducing Schnurri prevented the normal development of hypersensitivity after ultraviolet-induced injury, demonstrating that Schnurri is required to activate the transcriptional program that increases nociceptor sensitivity following damage.
These complementary roles suggest a model in which the BMP pathway shifts the balance between repression and activation of target genes within the nociceptor nucleus. When Brinker-mediated repression is lost, nociceptors become overly sensitive; when Schnurri-mediated activation is impaired, nociceptors fail to mount an appropriate sensitizing response to injury. Together, the data identify Brinker-related transcriptional regulators as key molecular switches that control whether nociceptors return to baseline or remain in a sensitized state.
Because persistent nociceptive sensitization is a likely contributor to chronic pain, nuclear regulators in the BMP pathway represent promising targets for future pain-relief strategies. Targeting transcriptional control could enable more selective interventions that prevent or reverse maladaptive sensitization without broadly suppressing sensory function. These findings also open possibilities for identifying individuals at higher risk for chronic pain and for designing precision therapies that normalize transcriptional responses after injury.
About this pain research news
Author: Press Office
Source: University of New England
Contact: Press Office – University of New England
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Original Research: Closed access.
“The brinker repressor system regulates injury-induced nociceptive sensitization in Drosophila melanogaster” by Geoffrey Ganter et al., Molecular Pain
Abstract
The brinker repressor system regulates injury-induced nociceptive sensitization in Drosophila melanogaster
Nociceptors detect potentially harmful mechanical or thermal stimuli and trigger protective pain responses. After injury, the nociceptor activation threshold decreases and pain signaling increases — a phenomenon known as nociceptive sensitization. While this process normally resolves with healing, persistent sensitization can drive chronic pain. Using Drosophila as a model, the study demonstrates that nuclear components of the BMP signaling pathway critically regulate sensitization. Knockdown of the Brinker repressor in nociceptors causes hypersensitivity without injury, whereas knockdown of the transcriptional activator Schnurri prevents injury-induced allodynia. These findings position Brinker-related transcription regulators as central determinants of nociceptor sensitivity and identify them as candidate targets for novel pain therapies.