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Nociceptors use multiple neurotransmitters to drive pain
Donald Iain MacDonald1, Rakshita Balaji1, Alexander T Chesler1,2
1National Center for Complementary and Integrative Health (NCCIH), National Institutes of Health, Bethesda, MD 20892, USA.
Biorxiv : the Preprint Server for Biology
|September 18, 2025
Summary
Nociceptors transmit pain signals using both glutamate and neuropeptides. Blocking both pathways in mice eliminated pain sensation, revealing neuropeptides as key pain transmitters.
Area of Science:
- Neuroscience
- Pain Research
- Molecular Biology
Background:
- Nociceptors are crucial for detecting harmful stimuli.
- Their role in pain transmission is complex, involving various signaling molecules.
- Previous studies suggested but did not confirm the necessity of specific pathways.
Purpose of the Study:
- To investigate the distinct and combined roles of glutamate and neuropeptides in nociceptive signaling.
- To determine if neuropeptides function as essential pain transmitters.
- To elucidate the redundancy in nociceptor communication.
Main Methods:
- Genetic approaches were used to selectively suppress glutamate transmission in nociceptors.
- Neuropeptide signaling was inhibited individually and in combination with glutamate suppression.
- Pain responses in genetically modified mice were assessed.
Main Results:
- Blocking either glutamate or neuropeptide signaling alone did not abolish pain responses.
- Simultaneous blockade of both glutamate and neuropeptide transmission led to profound pain insensitivity.
- This insensitivity mimicked the effects of complete nociceptor ablation.
Conclusions:
- Neuropeptides are confirmed as bona fide pain transmitters.
- Nociceptor signaling exhibits significant redundancy.
- This study resolves key questions regarding pain communication pathways to the brain.
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