Posted on Leave a comment

Pain, hyperalgesia and activity in nociceptive C units in humans

Pain, hyperalgesia and activity in nociceptive C units in humans


Check out this great bit of work by LaMotte et al from 1992.
Here’s some simple reflections of the science:
– First they’re exploring activity of nociceptors in humans. That means someone volunteered for this!
– They use a crude way of ‘finding’ C-mechanoheat nociceptive units (CMHs) – scrape the skin or pinch it between the fingers
– It is only classified as a C-fibre if the conduction velocity is less than 2 m/s
– It is only classified as mechanoheat nociceptor if it selectively responds to technical or heat stimuli which typically cause pain
– They carefully map the receptive field
– Then they inject capsaicin i.e. the active component of chili peppers
– Interestingly, they tried to limit the numerical rating scale of pain to sensation only (is it possible to separate yourself from the unpleasantness or tolerability?)
What did they find?
– Heat and pain threshold reduced after injecting capsaicin. Now temperatures as low as 30C were felt as painful!
– Cooling the skin reduced pain and the spontaneous firing of the CMHs
– Warming increased this again!
– There was evidence of mechanical hyperalgesia i.e. increased pain to mechanical stimuli
– Some of this was outside of the skin zone affected by the injection i.e. ‘secondary hyperalgesia’
– There was evidence of analgesia around the injection site too
A simple summary:
– Ask a bunch of crazy people if it’s ok to inject some chili into them
– Scrape, pinch, electrically stimulate, heat and cool them whilst asking if it hurts
– Find that the injection makes these things simultaneously hurt more or less depending on where you do it
– Then discover something totally cool but keep in under wraps
Here’s the cool discovery – hang in there!
“A few presumably chemosensitive C units were discovered serendipitously during studies of CMH units….” In other words, it looks like these researchers were (?) the first to discover sleeping or silent nociceptors in humans. BOOM
It’s worth hearing their summary and considering some of the current proposed models to understand pain with.
“An interesting question is why pain from intradermal injection of [capsaicin] is so intense….One possible explanation might be that the discharge pattern in C polymodal nociceptors on capsaicin injection is irregular, with bursts of impulses …. It is conceivable that such high instantaneous firing rates during bursts of impulses could give rise to considerable pain due to temporal summation….It is also possible that several types of nociceptors are activated by capsaicin. Candidate nociceptors in addition to the CMHs could include purely chemosensitive units as well as the heat nociceptors that respond both to noxious heat and to capsaicin but not to mechanical or cold stimuli.”

Research papers

You can access Lemotte’ paper here

Posted on Leave a comment

Central Sensitization: Viewpoints in JOSPT


This article is recently published in JOSPT – (here)


Central sensitization is a physiological mechanism associated with enhanced sensitivity and pain responses. At present, central sensitization cannot be determined directly in humans, but certain signs and symptoms may be suggestive of it. Although central sensitization has received increasing attention in the clinical literature, there is a risk that certain distinctions are being lost. This paper summarizes current knowledge of the physiology of central sensitization and its possible manifestations in patients, in order to inform a debate about the relevance of central sensitization for physical therapists. It poses 6 challenges associated with the application of central sensitization concepts in clinical practice and makes suggestions for assessment, treatment, and use of terminology. Physical therapists are asked to be mindful of central sensitization and consider potential top-down as well as bottom-up drivers, in the context of a person-centered bio- psychosocial approach.

Key Points

  • Central sensitization is a physiological and reversible mechanism associated with enhanced sensitivity and pain responses.
  • Until better markers are available, detection of central sensitization in humans remains tentative.
  • We must be careful that the concept of central sensitization is not used interchangeably with psychological manifestations.
  • Let us keep an open mind about central sensitization as our knowledge about this in

About the author

Matt Low

Matt is a Consultant Physiotherapist in the NHS and is a visiting associate at the Orthopaedic Research Institute at Bournemouth University. He qualified from the University of Southampton and is a member of the Musculoskeletal Association of Chartered Physiotherapists (MACP) following completion of his Masters degree in Neuromusculoskeletal Physiotherapy at the University of Brighton.

Matt has lectured and examined for pre-registration and post-registration students at a number of Universities in the South of England. He has lectured on subjects such as motor control, spinal manipulation and clinical reasoning skills. He has interests in compassionate person-centred care, the theory of causation within the healthcare setting, philosophy, reflective practice and critical thinking skills.


Matt will join us in the future for a f2f course. This particular article is a great pre-read for Melissa Farmer’ talk in Le Pub Home Brew

Posted on Leave a comment

Part 2 – Melissa Farmer on Central Sensitization

The Original Phenomenon, Play by Play

Under normal circumstances, a nociceptive signal reflects the features of a noxious stimulus. With central sensitization, nociception reflects altered excitability of a spinal cord circuit.

In this way, central sensitization marks the first point when nociception becomes independent of the environment.

Over 35 years ago, Clifford Woolf formally confirmed a hypothesis that had been floating around in the pain literature for many decades. Pain physiologists had long suspected that nociceptive signals could somehow be amplified in the spinal cord, but they didn’t have the technology to understand how this could happen. A major challenge was differentiating spinal-specific effects from peripheral nociception and how the brain processes this nociceptive information.

Woolf later described how the idea for this seminal experiment came to him. Keep in mind that electrophysiologists like Woolf spent their days in tiny, pitch-black rooms, subtly moving electrodes over tissue as they listened to neuronal spike trains like this. So just imagine a man sitting in the dark, pinching rat toes, and listening to intermittent static…and actually learning something. Woolf said:

“I found that most cells responded only to pinch or noxious heat of one or more toes. Some, however, had very large receptive fields encompassing the whole leg and could be driven by innocuous mechanical stimuli… It took me several months of recording to finally realize that [the neurons with large receptive fields] were only recorded at the end of the day, after the repeated noxious stimulation…. This was my ‘eureka’ moment…cells that had somehow changed as a result of the repeated input I had applied.”
Clifford Woolf

In other words, Woolf found that pinching rat toes all day provided just the right kind of repeated noxious stimulation that changed the rules of normal nociception. A toe pinch that evoked a modest withdrawal response in the morning created unexplainably large areas of hind limb hypersensitivity in the afternoon. Incredibly, normal (innocuous) stimuli applied to the hind limb also evoked withdrawal behaviors in the afternoon. He had somehow changed the way spinal interneurons were processing sensation!

If you want to feel a pang of sadness right now, listen to the spike train video again and reflect on your life’s accomplishments.

Deconstructing The Circuit

In science, there is a standard strategy for determining the conditions that are necessary and sufficient for a complex system to produce a behavior (like a rodent producing a “pain” behavior). You systematically inhibit parts of the system and determine whether behavior is affected.

This is like the way you diagnose computer problems: did the power supply die? Is there a loose screw jostling your motherboard? Are any wires frayed? If you replace a cable, is the function restored?

Or the way you troubleshoot a recipe gone wrong: Did you combine the ingredients in the right order? Was the oven preheated? Did you overmix the dough?

Like you, Woolf reasoned that if he wanted to understand the spinal cord’s unique role in pain hypersensitivity, he would need to control other confounding factors that also impact nociception: the brain and peripheral nociceptors.


Nitty Gritty Study Design

If details don’t interest you, skip to the final sections for an overview of study findings.

But if you want to get a strong grasp of mechanisms underlying central sensitization, and if you want to critically interpret the quantitative sensory testing (QST) studies that claim to measure central sensitization, read this section carefully.

Let’s start with the big picture and break down Woolf’s experimental approach:

1. The thermal injury.

One leg of each rat was exposed to 75ºC radiant heat for 60 seconds to create a thermal injury.

Why radiant heat?

When you’re interested in nociception, it’s ideal to have a “pure” stimulus. Radiant heat is appropriate for two reasons:

  • C-fiber nociceptors are responsible for detecting noxious heat, so Woolf knew exactly what type of nociceptor was being activated.
  • He didn’t want other types of sensory neurons to influence his results. A thermode placed on the rat’s skin would be a noxious heat AND pressure stimulus. Radiant heat takes pressure out of the equation. Woolf could then be certain that the subsequent effects would only be caused by C-fiber nociception.

Why 75ºC radiant heat for 60 sec?

I don’t know. This temperature is blistering hot, and a 60 second exposure time sounds brutal. I assume Woolf wanted to create an injury that was severe enough to clearly track the onset and gradual recovery over the next 24 hours.


2. The noxious stimuli.

Hot water.

Hot water very quickly warms the surface temperature of the skin in a uniform way. In contrast, the surface temperature of contact thermodes can sometimes differ from the temperature they are supposed to deliver.

A measure of heat hyperalgesia.

Mechanical stimulation.

To a rat, von Frey hairs pressed against the skin is like someone poking you with the pointy end of an umbrella. Not pleasant. Both the rat and you will quickly withdraw when you are poked.

A measure of mechanical punctate hyperalgesia. (Note: punctate = pinprick, which is considered a subset of tactile  or  pressure  hyperalgesia.)


3. The response.

Animals can’t tell us they are in pain, so we have to rely on their behaviors to infer it. Since Woolf was interested in spine-specific mechanisms, he chose a spinally-dependent behavior. He reasoned that the amount of noxious stimulation needed to produce a withdrawal reflex is also the amount of noxious input that usually gives rise to pain perception. So he narrowed in on the flexion withdrawal response, which is a fancy way of describing a rapid lift of the hind paw.  Flexion is considered a nocifensive (guarding/avoidance) behavior that occurs before nociceptive information can even reach the brain. It’s a reasonable behavioral proxy measure for pain in rats.

Woolf then recorded directly from bicep femoris (lower) motor neurons, which enable flexion withdrawal behavior. Motor neurons are efferent neurons controlled by local spinal circuits. These neurons are responsible for the muscle contractions that withdraw the hindlimb from noxious input.

Specific to spinal cord circuits?  CHECK.

Specific to noxious stimulation?  CHECK.



Brain Be Gone (sort of)

Woolf first sought to determine if the spinal enhancement of nociception required the brain. To do this, he removed the cerebellums of rats (decerebration) in his experiment to accomplish three goals:

  1. Preserve the spinal and brain stem reflex behaviors (like flexion);
  2. Prevent advanced reflex integration by the brain (which can actually exaggerate spinal reflexes because they are no longer inhibited by the brain);
  3. Preserve the rats’ abilities to generate nocifensive behaviors (withdrawal behavior, vocalizations, stimulus orientation), which is necessary to infer that noxious stimuli are intense enough to cause pain.

Woolf wanted to ensure that intact and decerebrated rats showed similar baseline sensitivity (measured by hind limb withdrawal) to the noxious mechanical and thermal stimulation he would use for his experiments. Figures 2.1 and 2.2 confirm this.


2. A low level of neural activity continued after the stimulus stopped. This was the first evidence of stimulus-independent spinal activity, which is also one of the three key features of central sensitization.

When Woolf looked at 25 different biceps femoris motor neurons to see if this was a generalized response, he realized that this ongoing neural activity was steadily increasing over the course of an hour!

Fig 2.4  Neural recordings from 25 motor neurons showed a steady rise in spontaneous neural activity following thermal injury. Adapted from Woolf, 1983.

He noticed that as the ongoing neural activity following the stimulus continued to increase, mechanical sensitivity steadily changed as well.  He wondered…could mechanical (punctate) hyperalgesia somehow be related to the spontaneous activity he was observing?

Fig 2.5  Both the injured hind paw (red) and unaffected hind paw (blue) exhibited mechanical (punctate) hyperalgesia lasting less than 60 minutes after the thermal injury. Adapted from Woolf, 1983.

Identifying the Culprits

Woolf wanted to know how different types of nociceptors were contributing to this effect. He used his knowledge of nerve structure and function to make this happen.

Different types of nociceptors transmit information at different rates (called conduction velocity). These transmission rates are controlled by the diameter of the nerve, which determines how quickly action potentials can be generated and therefore how quickly a nociceptor can fire. C-fiber nociceptors transmit information very slowly because they have small diameters and no myelin to speed up the signal. Nerves encased in myelin (like A-delta nociceptors) transmit information more quickly than unmyelinated C-fiber nociceptors. A-beta touch neurons transmit information most quickly due to their thick myelination. Julius & Basbaum (2001) have an older but still exceptional review of these principles.

Fiber types
Fig 2.6 Structure and function of primary afferent fibers. Adapted from Julius & Basbaum, 2001.


For example, myelinated A-delta nociceptor signals reach the brain more quickly than signals from unmyelinated C-fiber nociceptors. This is why A-delta mediated sharp pain is perceived before C-mediated dull, burning pain: simple differences in travel time.

Woolf decided to differentiate the contributions of different fiber types by looking at time delay signatures. He needed a precise noxious stimulus—in this case, electrical current to the sural nerve (which innervates the biceps femoris). By varying the intensity of this electrical current, he was able to selectively stimulate different groups of sensory neurons and their time delay signatures:

  • A-beta fiber activity was examined with repeated 100 micro-amp currents
  • A-beta and A-delta fiber activity was examined with repeated 250 micro-amp currents
  • A-beta, A-delta, and C fiber activity was examined with repeated 5 mA currents
Posted on Leave a comment

Central sensitization: Implications for the diagnosis and treatment of pain

Central sensitization: implications for the diagnosis and treatment of pain


What has central sensitization taught us about the nature and mechanisms of pain in patients, and what are the implications of central sensitization for pain diagnosis and therapy? Before doing this though, it is important first to understand exactly what central sensitization represents, how it has changed our general understanding of pain mechanisms, as well as reviewing the substantial data on central sensitization derived from studies on experimental pain in human volunteers. (from Woolf, 2011)

Key Points

A couple of questions to keep in mind:
1. What is central sensitisation?
2. Is central sensitisation present in people with pain?
First of all, what is central sensitisation?
– prolonged but reversible
– increase in the excitability and synaptic efficacy
– of neurons in the central nociceptive pathways
– which manifests as pain hypersensitivity
How is it induced?
– volunteers are subjected to various experimental noxious conditioning stimuli – applied to skin, muscles and viscera
What happens to these volunteers?
– they’re tested with various sensory stimuli before and after the conditioning stimuli
– if central sensitisation is present they manifest with pain hypersensitivity
What is pain hypersensitivity?
– pain on normally non-painful stimuli (allodynia)
– increased pain on normally painful stimuli but outside of the area of damage (secondary hyperalgesia – receptive field expansion)
– pain that continues after the stimulus (aftersensations)
– when a painful stimuli is repeated it gets more painful (enhanced temporal sensation)
What did this do to our understanding of pain?
“Pain we experience might not necessarily reflect the presence of a peripheral noxious stimulus.”
“Central sensitisation represents an uncoupling of the clear stimulus response relationship that defines nociceptive pain.”
“..noxious stimulus while sufficient was not necessary to produce pain.”
So, central sensitisation can be robustly and readily produced in volunteers in response to noxious stimuli.
Is the hypersensitivity that is seen in many pain states attributable to central sensitisation?
To answer these questions we need to know what measures accurately demonstrate the presence of central sensitisation. In the laboratory researchers commonly used the nociceptive withdrawal reflex and imaging as objective markers.        
However, it is unlikely that clinicians will be able to use these.
Are there specific subjective measures that suggest the presence of central sensitisation? Does the spreading of symptoms or elicitation of pain on normally non-painful stimuli suggest central sensitisation is present? Some interesting questions to have in mind whilst reading through this interesting review.

Research papers

You can find the full paper here, but there is plenty more to read en learn. We have a nice collection  of information on central sensitization here.

Posted on Leave a comment

Dr. Melissa Farmer at Le Pub Home Brew

Why should you listen to me? Why do I think I have all the answers? I base my confidence on seven (looooong) years of graduate training at McGill University, which is renowned for the pain research program founded by the pain pioneer Ron Melzack. It is a rich multidisciplinary environment where basic scientists attend clinical rounds, where clinicians combine adventurous creativity with pain-mechanism based approaches, and where I developed mouse models of chronic pain based on my patient observations in the clinic. And as a clinical psychology trainee in a multidisciplinary chronic pain clinic, I have been exposed to a wide spectrum of pain populations and bizarre symptom presentations that no longer phase me.

Painless complex regional pain syndrome, anyone? I’ve seen it.

I have embraced many opportunities to listen to people smarter than myself discuss pain mechanisms: graduate courses on acute and chronic pain physiology, lectures by major figures in pain research, drunken conversations at rowdy IASP parties. And as a postdoc, I trained with a brilliant pain neuroimager whose science is 5+ years ahead of the field. So I know some things about pain.

Dr. Farmer is a Research Assistant Professor in the Physiology Department of the Northwestern University Feinberg School of Medicine in Chicago.

Melissa Farmer, a clinician-scientist with roots in sexology, pain research, and neuroscience who is based in Northwestern University’s Feinberg School of Medicine in the Department of Physiology, as a Research Assistant Professor. Her doctorate in Clinical Psychology was obtained from McGill University, where she pursued human and animal research related to chronic pain. She specialises in translational research approaches, including cross-species analysis of cognition, emotion, and pain perception across multiple levels of analysis (cellular, systems, behaviour, animal model development, psychophysiology, clinical psychological assessment/treatment, multimodal neuroimaging).

Dr. Farmer’s current interests include:

  • Deciphering mechanisms underlying complex pelvic pain;
  • Fear memory formation/reconsolidation of visceral pain; and
  • Development of pain neuroscience education for non-scientists.

Meet Melissa in the video below:

Posted on Leave a comment

The role of C fibres in the generation of an increase in the flexor response to noxious stimuli

The role of C fibres in the generation of an increase in the flexor response to noxious stimuli

More for the thirsty (for knowledge) pain geek! Clifford Woolf and Pat Wall probing the role of C fibres in the generation of an increase in the flexor response to noxious stimuli.In other words:

– Suck some brain out of rats but keep enough in so they are still technically alive.

– Pick one of 3 different methods that will strongly stimulate (conditioning stimuli) the nerves – electrocute, irritate with a chemical, make the muscle work really hard for a long time

–  Look at how the rat responds before and after they’ve been conditioned with these stimuli- Then find out what happens if you block the nerves – before and after the conditioning stimuli

–  Demonstrate that the increased response to a noxious stimulus long after the conditioning stimuli has a strong central (in the spinal cord) component

–  Call this heterosynaptic facilitation- Wonder if these mechanisms have any baring on people experiencing chronic painIn their words:”Peripheral activation of C-afferents will modify the functional response of the spinal cord to other inputs applied long after the conditioning input, and this may be responsible for some of the sensory and motor alterations found after peripheral tissue injury.”

“The excitability increase is heterosynaptic because a conditioning stimulus in one group of primary afferents increases the response to other groups of afferents.”

“The presence of widespread tenderness (allodynia) with disordered movement is frequently the most disturbing symptom in patients in chronic pain. Therefore, the phenomena we report here deserves further attention as a possible model of a particularly distressing human state.”


Check it out!

Posted on Leave a comment

A Primer for the curious by Melissa Farmer

A Primer for the curious by Melissa Farmer

This four-part series on central sensitization is intended for clinicians, researchers, students, patients, laypeople, and any health care professional who values empirical evidence over blind conjecture when discussing mechanisms of chronic pain.

This is a pain mechanisms-heavy piece but don’t let that intimidate you. In 2004, I knew none of these things. So my goal is to shrink wrap 15 years of knowledge and experience into a neat summary that helps you to navigate the pain literature, conference lectures, and social media conversations with more confidence. Yes, there is some technical language that some may find challenging. I read stuff I don’t understand all the time, so don’t sweat it! The technical parts are followed by summary statements that will reinforce what is worth remembering.

Let’s Start from A Beginning

To treat chronic pain, we ideally need to understand what initiates and  maintains it. The biopsychosocial model is a cornerstone for organizing such efforts because pain is a conscious experience that reflects sensory input, our cognitive-emotional models of the world, sense of self in space, and self in relation to others. This particular piece will focus on one of many biological processes that impacts the strength and persistence of nociceptive signals that can contribute to pain perception: central sensitization.

The misinterpretations of central sensitization have reached epidemic proportions. As a clinical psychologist with training in chronic pain physiology, quantitative sensory testing, and neuroimaging, I find this continuing trend of misinformation to be a dangerous hurdle for translating basic science to patient care. If you have tried to read the literature on central sensitization and feel more confused than ever, I GET IT. Basic scientists in the pain field have done a poor job in communicating their findings in a way that is accessible to the clinical audiences who need the information most. Moreover, many clinical researchers and clinicians have not held one another accountable for misinterpretations of the concept. The problem is that many people have not invested their energy into carefully studying the concept prior to propagating these distorted ideas.

Instead, misinterpretations of central sensitization have been disseminated like a disastrous game of “telephone.” Who suffers the consequences? The health care professionals whose clinical care is informed by these reverberating half-truths, and the patients who are assessed and treated according to flawed logic.

A Brief Aside

Why should you listen to me? Why do I think I have all the answers? I base my confidence on seven (looooong) years of graduate training at McGill University, which is renowned for the pain research program founded by the pain pioneer Ron Melzack. It is a rich multidisciplinary environment where basic scientists attend clinical rounds, where clinicians combine adventurous creativity with pain-mechanism based approaches, and where I developed mouse models of chronic pain based on my patient observations in the clinic. And as a clinical psychology trainee in a multidisciplinary chronic pain clinic, I have been exposed to a wide spectrum of pain populations and bizarre symptom presentations that no longer phase me.

Painless complex regional pain syndrome, anyone? I’ve seen it.

I have embraced many opportunities to listen to people smarter than myself discuss pain mechanisms: graduate courses on acute and chronic pain physiology, lectures by major figures in pain research, drunken conversations at rowdy IASP parties. And as a postdoc, I trained with a brilliant pain neuroimager whose science is 5+ years ahead of the field. So I know some things about pain.

Ideological Disclaimer

I approach the topic of central sensitization from a basic science perspective that adheres closely to the original phenomenon first described by Clifford Woolf (1983). I see this as an appropriately conservative perspective that prioritizes empirically-derived knowledge of pain mechanisms over speculation, even clever  speculation. Regarding central sensitization in clinical contexts, I do think that this can be deduced from certain symptom patterns but I am swayed only by reasonable evidence that a patient’s symptoms are consistent with features of the original phenomenon. In the absence of such evidence, I find it irrational and dangerous to claim that we are certain about what central sensitization can and cannot “do” in a clinical setting.  Premature conclusions about pain mechanisms do not enrich clinical assessment or treatment. Rather, these speculations seem to restrict the clinical hypotheses that are considered and limit treatment.

I find it irrational and dangerous to claim that we are certain about what central sensitization can and cannot “do” in a clinical setting.

Melissa Farmer

With that said, I believe that peripheral, spinal, and brain mechanisms distinctly contribute to clinical pain, that their respective contributions could be deduced with proper evidence, and that such an approach will point to individualized multidisciplinary treatments  that actually relieve pain.

Nociception vs Pain

We can all agree that nociception and pain are not the same thing. However, studies in multiple species show a close correspondence between the magnitude of pain perception (or pain behavior in non-humans) and sensory neuron firing properties. For example, this classic microneurography study reveals that neural firing patterns of nociceptors closely track with perceived pain. This is the rationale underlying the idea that subjective pain perception (or “pain” behavior in animals) can be used to deduce general properties of neuronal function.

If you are interested in a general overview of nociception check this out by Ardem Patapoutian, the guy who discovered piezo receptors.  For physical therapists, you may want to check out a more specialized reference on muscle and nociception by the classic muscle physiologist Siegfried Mense.

The Game Plan

This discussion will approach central sensitization from many angles. Specifically, I will:

  1. Critically assess how the word “sensitization” is used and abused.
  2. Introduce the beginning of the cascade leading to central sensitization: peripheral nociceptor sensitization.
  3. Provide an in-depth walk-through of Woolf’s original 1983 paper.
  4. Highlight the essential features of spinally-mediated (“classical”) central sensitization.
  5. Critique and discuss common misinterpretations of spinally-mediated central sensitization.
  6. Contrast the beautifully specific mechanisms identified by Woolf with the misguided and hypothetical phenomena referred to as “central sensitivity syndromes,” “centralized pain,” “central hypersensitivity,” and similar variants of these terms.
  7. Offer advice on how to critically navigate existing and future literature on these topics.

Use and Abuse of “Sensitization” 

In biology, the term sensitization  describes a progressive enhancement of a response with repeated exposure to a stimulus. Sensitization is like the mounting frustration you feel when someone leans toward you, their finger wagging an inch away from your face, saying, “I’m not touching you! I’m not touching you! I’m not touching you!”  After the stimulus is gone, the frustration fades…as does sensitization.

It is an adaptive process rather than a mechanism per se.

Adaptations are achieved in different ways in the periphery, spinal cord, and brain. This means sensitization is not a process that can be generalized across nervous systems (check out a great paper on this perspective). For this reason, it’s important to preface the term “sensitization” with a location (e.g., peripheral sensitization, central sensitization), which reflects the location of the primary physiological mechanism(s) of sensitization. Stating that a patient is simply “sensitized” is mechanistically and clinically meaningless because such a statement contains no information about where (or whether!) sensitization is actually occurring. You will soon see why this distinction is needed when we attribute pain symptoms to the periphery versus spinal cord versus brain.

Sensitization is not a process that can be generalized across nervous systems

Melissa Farmer

The Hyperactive Nociceptor 

The most basic form of sensitization occurs in nociceptors in response to repeated or intense noxious stimulation. Inflammation is the most common “cause” of peripheral sensitization, which doesn’t say much because many things cause inflammation (noxious heat, repeated skin scratching, ultraviolet radiation, invading pathogens) and inflammation is a non-specific response.  In the pain literature, the discussion of inflammation is often limited to the notorious “inflammatory soup” that bathes the end of the nociceptor in a pool of molecules that change how responsive the nociceptor is to noxious input.

Instead of stopping at this level of detail, I want to take you a little further. Stating that a nociceptor is affected by inflammation doesn’t tell you how  it is affected. The how  is important for understanding the difference between peripheral and central sensitization. (Keep in mind that acute and chronic inflammation likely operate by different rules, as well.)

When a nociceptor is sensitized, its firing rules change. One new rule is that less noxious input is needed to for the nociceptor to generate an action potential (this may underlie reduced pain thresholds, or allodynia). Another new rule is that the magnitude of the neuron’s response may be amplified (leading to increased pain perception, or hyperalgesia). Yet another rule is that the nociceptor may fire randomly, even when there’s no noxious input detected at the nerve ending (which may further enhance allodynia or hyperalgesia, or contribute to “spontaneous” pain). I strongly recommend Gary Bennett’s superb piece on potential mechanisms of spontaneous pain.

These changes are triggered and maintained by neurochemical changes throughout the nociceptor, not only at the nerve ending. Therefore the increased nociceptor excitability (or hyperexcitability) that defines nociceptor sensitization may reflect multiple underlying processes near the site of injury.

Two noteworthy points before we move forward. First, allodynia and hyperalgesia can be generated by multiple mechanisms in the periphery, spine, and brainstem, so I’ve described one manifestation of many. Second, peripheral sensitization does not explain altered detection thresholds for heat, tactile, vibration, or any other sensory stimulus. Detection thresholds are determined by receptors at the end of sensory neurons (aka, the peripheral terminal). Finis.

Mechanisms of Peripheral Sensitization 

To date, five changes in nociceptor function have been linked with peripheral sensitization. These changes don’t necessarily occur at the same time and various combinations of these changes may be responsible for amped up nociceptor excitability depending on the type and/or severity of insult.

(a) Nociceptors have reduced activation thresholds due to changes in their membrane potentials (described here).

(b) The magnitude of nociceptor signaling is enhanced.

(c) A nociceptor spontaneously emits signals with no stimulus (i.e., ectopic discharges).

Xiao & Bennett used a common rat model of inflammatory pain (Complete Freund’s Adjuvant) to show that over 20% of  A-delta and C-fibers fire spontaneously (the effect normalized within a couple of weeks).

(d) The magnitude of nociceptor signaling is enhanced with repeated stimulation (wind-up).

(e) “Silent” nociceptors become active contributors to sensitization.

Silent nociceptors normally don’t respond to noxious mechanical stimulation (mechanically insensitive afferents). But during inflammation or with exposure to certain inflammatory mediators, they are “unsilenced” and begin firing in response to noxious mechanical input. Subsets of C-fibers nociceptors and A-delta nociceptors are unsilenced during peripheral sensitization.

Is Peripheral Sensitization Purely Peripheral?

Peripheral sensitization begins to ramp up activity in spinal cord neurons, which technically means that it also impacts part of the central nervous system. However, the initiating mechanisms underlying peripheral sensitization are rooted in the peripheral nervous system, and therefore any downstream effects are still considered peripheral in origin. This is why temporal summation (“wind-up”)—which reflects short-term increases in the excitability of spinal interneurons following the repeated stimulation of C-fiber nociceptors—is still considered a peripheral phenomenon. Researchers were able to dissociate the peripheral and spinal contributions to wind-up by delivering identical series of noxious pinprick or heat stimulation to the skin surface at a particular frequency to amp up C-fiber activity. Because the intensity of peripheral input was kept constant, they could dissociate pain perception related to the peripheral input (baseline) from the additional spinal amplification of the signal (following “wind-up”). However, wind-up requires stimulation of C-fiber nociceptors to persist. if you remove C-fiber input, the spinal interneurons will quickly return to their baseline states.

Wind-up happens in everyone. But in a subset of people with inflammatory, neuropathic, and/or other types of chronic pain, wind-up may occur more quickly than in healthy people and they report more intense peak pain. If a patient exhibits symptoms of enhanced wind-up, this is strong evidence of ongoing C-fiber nociception at/near the tissue that is being prodded…because without C-fiber stimulation, this phenomenon extinguishes. Importantly, absence of increased wind-up just means chronic pain is mediated by factors other than amped up C-fiber nociception.

Wait…Temporal Summation is Peripheral?

At this point, some readers may be reeling from the idea that wind-up is actually a peripheral phenomenon… For those who wonder why any sane person would “reel” from that idea, consider that wind-up is often cited as a proxy measure for central sensitization in the clinical literature.

There’s a logical reason why people think this, and a logical reason for why this belief is mistaken. It is true that enhanced wind-up is ONE of the MULTIPLE physiological changes observed with central sensitization. However, in the absence of the other hallmark features of central sensitization, wind-up is just wind-up . Alone, it is not a valid proxy for central sensitization. In contrast, if wind-up is enhanced AND there is clinical evidence of pinprick hyperalgesia or dynamic mechanical allodynia, I would consider it moderately strong evidence of current central sensitization. This means that the authors of all of those quantitative sensory testing studies that claim wind-up evidence is sufficient proof of central sensitization are lying to you and to themselves.

In the end, enhanced wind-up can only tell us that spinal nociception is abnormal, nothing more. It is one clue that the degree of peripheral input has begun to affect the excitability of spinal cord interneurons, which is the first of many steps toward central sensitization. The only thing that will return the nociceptor to its baseline state is a lack of noxious input, disabling the capacity of the nociceptor to fire (via lidocaine, bupivaine, etc), or disrupting the molecular changes that enhance nociceptor excitability. Even then, it takes some time for the nociceptor’s excitability to return to its normal level.

Uses of the Term “Central Sensitization”

Part of the confusion surrounding central sensitization is that people use the term in different ways, and only one of these uses is supported by empirical evidence. Three definitions of central sensitization are currently used in clinical and scientific settings.

1. Spinally-Mediated Central Sensitization

Clifford Woolf’s original term central sensitization describes quantifiable changes in the excitability of spinal cord neurons. This definition is rooted in experimental evidence that has been replicated by many international laboratories over dozens of years. It is fantastically precise in the pain symptoms it can explain.

2. IASP’s Definition 

Increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input.”

I don’t agree with IASP definition of central sensitization and I’ll tell you why.

IASP’s revised term expands Woolf’s observations to all nociceptive neurons in the CNS, despite:

(i) There is minimal evidence of nociceptive-specific neurons in the CNS. In over 50 years of pain science, less than 300 nociceptive-specific neurons  have been identified across different animal studies. You slough off more dead skin cells washing your hands. Note that if a study does not also evaluate a neuron’s response to non-nociceptive stimuli, it cannot be considered specific to nociception. That’s how science works.

Most recently, Iannetti’s group showed that the “pain matrix”—a mythical group of brain regions that was thought to be necessary and sufficient to create the conscious perception of pain—is not specific to pain when the appropriate control tasks are included to account for stimulus intensity and variability.

(ii)  No data in the neuroscience literature indicates that spinal and cortical neurons adapt to information in the same ways. Ted Price covers this issue beautifully and I refer the gentle reader to his work.

(iii)  The spine and the brain are not so physiologically similar that they can be haphazardly grouped together just because they are both part of the central nervous system. This is the logical equivalent of saying that the visual cortex and the cerebellum are functionally equivalent because they are both made of neurons. The field of neuroscience is based on understanding specialization within the nervous system and appreciating why different structures follow different rules of engagement. We can’t mix and match parts of the central nervous system.

My impression is that this false equivalence is symptomatic of the biased pain researchers who developed the IASP definition of central sensitization (the IASP Task Force on Taxonomy). From what I can tell, there were no Task Force members who had the expertise to make such an assertion.

Instead, this perspective also betrays a gross disinterest in how the brain uniquely mediates pain perception.

(iv)  The IASP taxonomy comes with an important caveat: “It is important to emphasize…that the terms have been developed for use in clinical practice rather than for experimental work, physiology, or anatomical purposes.”

And now comes the most popular use of the term…

3. A Hypothetical Umbrella Term

A term used to describe any type of change within the CNS that could lead to enhanced pain perception. This use of the term reflects a very limited understanding of Woolf’s original concept and limited understanding of chronic pain physiology, yet it is the most popular use of the term as the putative mechanism underlying the dubious “central sensitivity syndrome.” I strongly believe that this is the most harmful misuse of the term and I’ll be going into some detail about how this came to pass.

How Did We Get Here?

To understand how the ideas of central sensitization have evolved and mutated, our next step is to revisit the original phenomenon.  In Part 2, I will describe the findings of Woolf’s original paper so you can understand the basic phenomenon.

In Part 3, the most common clinical misinterpretations of central sensitization will be critically examined.

In Part 4, awful logic underlying the conception of “Central Sensitivity Syndrome” will be ruthlessly interrogated.


This blogpost was originally posted on