Which neurotransmitters are rapidly and repeatedly released to generate pain signals (select all that apply)?

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Neurotransmitters Rapidly Released to Generate Pain Signals

The neurotransmitters that are rapidly and repeatedly released to induce pain are: Glutamate, Substance P, and Calcitonin gene-related peptide (CGRP). 1

Primary Excitatory Neurotransmitters in Pain Transmission

Glutamate (Correct Answer)

  • Glutamate is the principal excitatory neurotransmitter released by primary afferent neurons at the spinal dorsal horn during nociceptive transmission. 1
  • Glutamate is released from presynaptic neurons and captured by secondary neurons to transmit pain signals to supraspinal regions. 1
  • In chronic pain states, prolonged noxious stimulation leads to enhanced neuronal firing and increased release of glutamate at the spinal dorsal horn. 1
  • Glutamate is present in the terminals of small diameter primary afferent fibers and dorsal horn interneurons, playing a critical role in spinal nociceptive transmission. 2
  • Glutamate acts on NMDA receptors to mediate excitation and can induce spinal sensitization, which is key to maintaining neuropathic pain and hyperalgesia. 2, 3

Substance P (Correct Answer)

  • Substance P (SP) is a neuropeptide that is rapidly released alongside glutamate during enhanced neuronal firing in pain states. 1
  • The evidence explicitly states that chronic pain involves "increased release of neurotransmitters and amino acids at the spinal dorsal horn (e.g., glutamate, CGRP and SP)." 1
  • Substance P acts as a primary afferent neurotransmitter or modulator of nociceptive information. 4
  • Substance P infusion increases the release of excitatory amino acids including aspartate and glutamate, supporting its role in nociceptive transmission. 4

Calcitonin Gene-Related Peptide/CGRP (Correct Answer)

  • CGRP is explicitly identified as one of the neurotransmitters released with increased neuronal firing during chronic pain states. 1
  • CGRP is released together with glutamate and Substance P at the spinal dorsal horn during prolonged noxious stimulation. 1

Neurotransmitters NOT Involved in Rapid Pain Transmission

Aspartate (Incorrect Answer)

  • While aspartate is an excitatory amino acid that can be released during nociceptive stimulation, it is not among the primary neurotransmitters emphasized in rapid pain transmission. 4
  • Aspartate release has been demonstrated following formalin injection and Substance P infusion, but it is not highlighted as a primary rapid pain transmitter in the guideline evidence. 4

Serotonin (Incorrect Answer)

  • Serotonin functions as an inhibitory neurotransmitter in descending pain modulation pathways, not as a transmitter that induces pain. 1, 5
  • Serotonin is a critical transmitter of the descending inhibitory system that modulates nociceptive information at the spinal dorsal horn by reducing neurotransmitter release from primary afferent neurons. 1
  • Serotonin plays a key role in descending pain inhibitory pathways that suppress rather than generate pain signals. 5, 6

Clinical Context and Mechanism

  • The rapid and repeated release of glutamate, CGRP, and Substance P sensitizes postsynaptic neurons and activates microglia and astrocytes toward neuroinflammatory states. 1
  • This enhanced release contributes to central sensitization, where nociceptive pain becomes amplified and diffused, potentially leading to chronic pain conditions. 1
  • The balance between excitatory transmission (glutamate, Substance P, CGRP) and inhibitory systems (serotonin, noradrenaline, GABA) determines the level of pain transmission. 3

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

2
Research

[N-methyl-D-aspartate (NMDA) receptor and pain].

Masui. The Japanese journal of anesthesiology, 1996

5
Guideline

Neurotransmitter Functions and Clinical Significance

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

6
Guideline

Spinothalamic Tract Function and Clinical Significance

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

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This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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