How the Brain's Chemical Signaling System Controls Substance P Pain Release | Research

The takeaway

The cAMP signaling pathway mediates substance P release in the spinal cord through both PKA and Epac2 mechanisms, with Epac2's contribution lost during chronic pain states.

Epac2 pathway selectively lost in chronic pain
While PKA-mediated substance P release remains intact during latent pain sensitization

What the researchers found

cAMP drives substance P release through dual PKA and Epac2 pathways, but Epac2's contribution is selectively lost during latent pain sensitization, potentially reflecting chronic pain-related neural remodeling.

Why it matters

Understanding the specific signaling cascades that control substance P release could identify new therapeutic targets for chronic pain that are more selective than broadly acting painkillers.

The numbers in context

PKA phosphorylates NR1 + NR2B; Epac2 via Raf-MAPK; TRPV1/TRPA1 not involved; Epac2 effect lost in latent sensitization

How the study worked

Rat spinal cord slice preparations with NK1R internalization as a measure of substance P release. Pharmacological manipulation with cAMP analogs, pathway inhibitors, and NMDA antagonists. Calcium imaging in cultured dorsal horn neurons. Latent sensitization pain model.

Who was studied

Rat spinal cord slices and cultured dorsal horn neurons

What this study cannot tell us

Rat spinal cord slice preparations may not fully reflect in vivo pain processing. Pharmacological tools may have off-target effects. Latent sensitization model is one specific chronic pain paradigm.

How to read the evidence

Detailed mechanistic study using multiple complementary pharmacological and imaging approaches. Strong basic science evidence.

When this study was published

Published in 2021, advancing understanding of spinal cord pain signaling mechanisms.

The bigger picture

Chronic pain affects over 1.5 billion people globally. This study reveals that the signaling controlling substance P release changes during chronic pain, suggesting that treatments effective for acute pain may not address the altered mechanisms driving chronic pain conditions.

Questions still open

Could Epac2-specific modulators provide new chronic pain treatments?
Why is Epac2 signaling lost during pain sensitization?
Do similar pathway changes occur in human chronic pain conditions?

Common questions

What is substance P and why does it matter for pain?

Substance P is a neuropeptide that transmits pain signals in the spinal cord. When released from nerve endings, it activates NK1 receptors that amplify pain signaling to the brain. Understanding what controls its release could lead to better pain treatments.

Why does chronic pain differ from acute pain at the molecular level?

This study found that one of the two signaling pathways (Epac2) that normally controls substance P release is lost during chronic pain states, while the other (PKA) remains active. This means the neural circuits controlling pain are physically remodeled, which may explain why chronic pain is harder to treat than acute pain.

Read the original research

cAMP signaling through protein kinase A and Epac2 induces substance P release in the rat spinal cord.

Neuropharmacology, 189, 108533

View on PubMed ↗Publisher’s paper ↗

Citation

Chen, Wenling; McRoberts, James A; Ennes, Helena S; Marvizon, Juan Carlos. (2021). cAMP signaling through protein kinase A and Epac2 induces substance P release in the rat spinal cord.. Neuropharmacology, 189, 108533. https://doi.org/10.1016/j.neuropharm.2021.108533