Central sensitization: analysis by physio meets science.
Neurophysiological Mechanism of Central Sensitization in the Spinal Cord following Surgery:
▶️ Central sensitization was first described by Woolf in 1983 (https://pubmed.ncbi.nlm.nih.gov/6656869/) as a form of long-term adaptive neuroplasticity that amplifies the transmission of nociceptive information by affecting spinal cord neurons and is believed to be a principal neurophysiological mechanism with regard to pain persistence.
▶️ Peripheral nociception can trigger a prolonged increase in the excitability of dorsal root ganglia (DRG) neurons, which transmit nociceptive signals to the spinal cord, resulting in central sensitization.
▶️ This condition involves heightened responsiveness of spinal neurons, driven by signaling molecules like adenosine triphosphate (ATP) and neurotransmitters such as glutamate (Glu) and substance P (SP).
▶️ These molecules activate specific receptors on spinal neurons, including purinergic receptor 2 (P2-R), N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), and neurokinin 1 receptor (NK1R).
▶️ The activation of these receptors sets off a cascade of intracellular pathways involving enzymes like calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), protein kinase A (PKA), mechanistic target of rapamycin (mTOR), phosphoinositide 3-kinase (PI3K), and extracellular signal-regulated kinases 1/2 (ERK1/2), all of which amplify the transmission of nociceptive signals to the brain.
▶️ Additionally, spinal astrocytes and microglia play a role by releasing pro-inflammatory cytokines—such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor α (TNF-α)—and chemokines like fractalkine and chemokine (C-C motif) ligand 2 (CCL2).
▶️ These immune cells, via receptors like P2Y, chemokine receptor for fractalkine (CX3CR1), and colony-stimulating factor 1 receptor (CSF1-R), further intensify spinal neuron activation and sustain nociception. Over time, the persistent activation of these pathways can lead to chronic pain, marked by ongoing neuronal hyperactivity and heightened sensitivity.
▶️ Other factors involved include brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), colony-stimulating factor 1 (CSF1), metabotropic glutamate receptor (mGluR), reactive oxygen species (ROS), and tropomyosin receptor kinase B (TrkB).
- Physio Meets Science.
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Chronic pain after surgery, also known as chronic postsurgical pain (CPSP), is recognized as a significant public health issue with serious medical and economic consequences. Current research on CPSP underscores the significant roles of both peripheral and central sensitization in pain development and maintenance. Peripheral sensitization occurs at the site of injury, through the hyperexcitability of nerve fibers due to surgical damage and the release of inflammatory mediators. This leads to increased expression of pronociceptive ion channels and receptors, such as transient receptor potential and acid-sensing ion channels (ASIC), enhancing pain signal transmission. Central sensitization involves long-term changes in the central nervous system, particularly in the spinal cord. In this context, sensitized spinal neurons become more responsive to pain signals, driven by continuous nociceptive input from the periphery, which results in an enhanced pain response characterized by hyperalgesia and/or allodynia. Key players in this process include N-methyl-D-aspartate receptor and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, along with proinflammatory cytokines and chemokines released by activated glia. These glial cells release substances that further increase neuronal excitability, maintaining the sensitized state and contributing to persistent pain. The activation of antinociceptive systems is required for the resolution of pain after surgery, and default in these systems may also be considered as an important component of CPSP. In this review, we will examine the clinical factors underlying CPSP in patients and the mechanisms previously established in preclinical models of CPSP that may explain how acute postoperative pain may transform into chronic pain in patients.
Keywords: CHRONIC PAIN; Pain, Postoperative; Synaptic Transmission.
© American Society of Regional Anesthesia & Pain Medicine 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.