[Be patient. Blog Content is Under Construction!]

 

Have you ever found yourself asking questions like:

 

Are nociception and pain the same thing?

Can nociception occur without pain perception?

Is nociception necessary and sufficient for pain perception?

Can we feel pain without nociception?

 

If any of these questions have crossed your mind, you are in good company. Your curiosity about the relationship between nociception and pain intellectually unites you with decades of pioneering pain researchers. Our continued struggle with some of the most basic questions in pain science is a reminder that, in the absence of more data, it is incredibly difficult to philosophize about physiological processes. In other words, all the rationale dialogue in the world–about semantics, about various interpretations of nociception, etc–cannot reveal to us the true nature of pain physiology.

Ideas need data.

 

Why The Debate Matters to YOU

Some may consider this “debate” an unnecessary theoretical exercise. “Yes, nociception and pain are not the same thing,” they say, “But they are so often correlated with each another that they might as well be.” It’s a fair point. In humans and other species, there is a close correspondence between sensory neuron firing properties and magnitude of pain perception/behavior. Pain psychophysics is based on the assumption that we can use subjective pain perception to deduce the general properties of sensory neuronal function. In fact, decades of research based on this assumption have yielded important insights into the links between basic science research and the pain humans experience.

The nociceptor sensory neuron-pain perception link is useful when dealing with acute pain, pain with an injury, or pain with short-term local tissue inflammation. But chronic pain, by definition, outlasts local tissue damage and is therefore not fully represented by the activity of sensory neurons. So the nociception = pain perception assumption will sabotage your chronic pain management efforts.

The field of pain science has increasingly moved toward a mechanisms-based approach, which is essential for piecing together the causal relationships between peripheral, spinal, and brain changes that mediate the transition to and maintenance of chronic pain. Yet there remains an alarming disconnect between research and clinical care, and the false equivalence of nociception and pain is at the heart of this disconnect. Concepts used regularly in the clinic, such as hypersensitivity and sensitization, were first demonstrated by pain scientists who studied the firing patterns of single neurons in response to noxious stimulation. These phenomena are so complex that prominent researchers continue to study the biological events that are needed for their induction and persistence.

 

Critical Thinking and Pain Science 

For many people who follow the field of pain, bridging the gap between research and the clinic is a challenge. I believe this is because modern pain science requires an understanding of many types of scientific approaches, or levels of analysis. Pain emerges from a long chain of molecular, cellular, systems, behavioral, and psychosocial events, and the interactions between these levels is key to appreciating the quirky ways that the body breaks its own physiological rules as pain becomes chronic.

I know this because I began learning about pain science when I was firmly embedded in the behavioral and psychosocial realms. During my graduate training in clinical psychology, I quickly realized that staying within my comfort zone limited the kinds of questions I could ask (and therefore the types of answers I could pursue). It also limited by ability to understand the beautiful complexities of chronic pain.

I am by no means a pain expert, but I am an expert translator. This blog is my attempt to empower you, the gentle practitioner, to better understand the core distinctions between nociception and pain through the eyes of a basic scientist who can speak clinician. Let’s begin.

 

Some Clarifications

I’ve noticed a few misconceptions that can skew discussions about nociception and pain. Let’s touch on those before we begin.

 

(A) There are various ways to ask whether nociception and pain are synonymous, but the way questions have been posed within these discussions have different implications.

The phrasing of a question matters. The following questions are not asking the same thing and must be considered separately :

        Can nociception occur without pain perception?

        Is nociception necessary and sufficient for pain perception?

       Can we feel pain without nociception?

 

(B)  The equation of nociception and pain with body and mind, respectively, is artificial. This dichotomy is not useful for answering the questions in (A).

Nociceptive signals are transmitted through the periphery, spinal cord, and brain. If the signal is disrupted at any point in this chain of events—even in brain regions like the brain stem or thalamus–the nociceptive input does not contribute to perception. So in the context of the above questions, let’s refrain from using the terms body and mind.

 I appreciate that nociception is often aligned with the function of neurons embedded in tissue and that’s why this comparison is continually made. But, “Is tissue injury necessary for pain perception” is NOT the same question as “Can we feel pain without nociception?” The former assumes that tissue injury is the only important cause of nociception, which is a logical error to begin with.

It is important to recognize that people often state extreme forms of arguments in order to get the basic point across. This should be considered in the context of their other communications.

 

(C)  What level of evidence is necessary to answer these questions?

As a scientist, when I see a question about nociception, the answer must be supported by evidence that has measured nociception. Nociception means that a signal related to potentially noxious info has been relayed from at least one nociceptive neuron to another nociceptive neuron. Pain perception doesn’t prove that nociception has occurred. Receptor binding at the end of a nociceptor doesn’t prove that nociception has occurred.

Only evidence and reasoning related to neurons that relay signals related to noxious stimuli—whether or not they are related to pain perception—are relevant to answer this question. This can include electrophysiology or microneurography data, or it can include fMRI data related to the application of noxious stimuli that can be dissociated from perception. It cannot be dependent on pain perception, proper, if we are sticking to the questions originally posed.

Again, the question demands this level of evidence to be answered. We cannot philosophize physiological processes. It doesn’t work that way. Therefore if an argument about nociception and pain that does not include evidence that nociception is actually happening, then that statement does not address the argument at hand.

 

(D)  Evidence that peripheral nociception contributes to initiation of pain doesn’t mean it is equally involved in pain maintenance, and vice versa.

This is particularly relevant for evidence that patients with chronic post-stroke pain (thalamic pain syndrome) who report pain that correlates with peripheral nociceptive input at some time point. This has 0% relevance for whether or not pain originating from a thalamic injury—a structure devoid of nociceptors—was initiated with normal nociception. The Haroutounian study, while excellent, cannot answer the critical questions related to the time point that is most critical for this condition (in relation to the current conversation), immediately post-stroke.

 

(E)  Evidence that a peripheral block diminishes pain for a short period of time does not mean that peripheral nociception must be responsible for pain.

A peripheral block does not impact spinal cord circuits that can have completely dissociable functional changes that contribute to nociception. And unless a study has a long-term follow-up, this evidence does not address relevance of peripheral nociception in chronic pain. Temporarily blocking peripheral nociception in a person whose pain is being distorted by spinal cord processes (e.g., referred pain/cross-talk, central sensitization) does not impacted the entire nociceptive pathway that can perpetuate chronic pain.

A Common Vocabulary

Semantics is an important issue in pain science.  Certain words are used in very specific ways (such as somatic, visceral, neurogenic inflammation, nociceptive pain, neuropathic pain, etc).  Every several years, the International Association for the Study of Pain (IASP) convenes a new task force to examine its definitions of pain terminology based on critical reviews of the recent pain literature and based on expert opinions from pain clinicians and basic scientists. The fact that these terms are revised over time reinforces that they are etched in stone by the Gods. With that said, certain terms are unlikely to be modified unless a dramatic, paradigm-changing scientific discovery rocks the pain world. Two of the terms that are etched in proverbial stone are the focus of this blog.

Pain: 

“An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”

Nociception:

“The neural process of encoding noxious stimuli.”

By extension, nociceptors are the sensory neurons that uniquely detect potentially harmful or threatening information in the environment.

IASP definitions often come with clarifying or conditional statements that suggest how the terms should and should not be used. These statements reflect current thought and are often refined over time. I like to imagine that a mischievous, sarcastic monkey writes these statements because they often cause more controversy than they solve.

Enter, the IASP Qualification Monkey:

Looks like a punk, doesn’t he?  He is.

Why We Equate Nociception and Pain

There is strong evidence in healthy people that individual nociceptor activity closely correlates with pain perception. In 1984, Shady, Torebjork & Ochoa used microneurography to stimulate individual nociceptors (“single identified sensory units”) in the hand and arm (median nerve or medial cutaneous nerve of the forearm).

Yet even the authors state that “all perceptual experience is the result of cortical processing of afferent signals, and central rather than peripheral factors may determine which signals are given priority” (pg 185).

Priorities

In order to determine the relationship between nociception and pain, it’s necessary to prioritize data that is minimally biased by confounding variables. Nociception is mediated by the primary afferent sensory neurons that detect noxious information, which  were named nociceptors. In the real world, a single nociceptor is rarely activated–it is more likely that a large noxious stimulus impacts a patch of skin that includes nociceptors and non-nociceptors. Even if a person perceives pain in this situation, the perception is confounded by concurrent activation of sensory nerves that are unrelated to pain. It is a flawed approach to examining the nociception-pain relationship.

The only method that measure the activity of individual nociceptors–unbiased by neural activity of other sensory neurons–is electrophysiology.

Electrophysiology is the study of electric activity in living biological tissues. Neurons share information with other neurons by generating electrical activity (called action potentials) that can be detected by the receiving neuron(s). Electrophysiology experiments are primarily conducted in laboratory animals; when conducted in humans, the term microneurography is used.

Microneurography involves the recording of nerve impulses by inserting a needle into myelinated or unmyelinated human nerves.

This historical review of microneurography is an excellent introduction to the intricacies of the method.

Quick (Technical) Primer on Nociceptors 

Three types of nerve fibers are responsible for transmitting innocuous (Aβ fibers) and noxious (Aδ and C fibers) sensory information. Normally, Aβ fibers transmit innocuous light touch, whereas C and Aδ fibers act as nociceptors that transmit different types of sensations that may lead to pain perception. Therefore our examination of nociception will focus on research conducted with C and Aδ fibers.

C and Aδ nociceptors come in different “flavors” that allow them to detect many types of sensory stimuli. These subtypes are classified according to their functional and structural features:

(1) nerve diameter (determines speed of activation and information transmission,

(2) the presence of myelination (also determines speed of transmission),

(b) stimulus modality (whether they respond to heat, touch, cold temperature, etc),

(c) patterns in neuron excitability (rate of neuronal firing, threshold of activation, adaptation profile),

(d) molecular markers that mediate these response properties, and

(e) functional properties unique to either somatic or visceral tissue.

These functional and structural features mean that each type of nociceptor has specific conditions needed for it to activate, or generate action potentials

Let’s look at how nociceptive signals begin. The word “encoding” is often used to describe the detection and conversion of energy from a stimulus to an electrical signal that the brain can decipher. Neuronal encoding consists of 3 critical steps:

1. Detection of a stimulus by sensory receptors or channels,
2. Transduction, or conversion, of this stimulus into neural impulses, and
3. Transmission of these neural impulses through the generation of action potentials. When a neuron is at rest, it isn’t transmitting any signals.

Collectively, these encoding properties determine how responsive, or excitable, a neuron is (called neuronal excitability). Nociceptive signaling therefore relies on specific conditions needed to generate action potentials. A stimulus that is capable of generating an action potential is called a threshold stimulus.

The different fiber types terminate onto secondary afferent neurons in different parts of the dorsal horn of the spinal cord, to 8 layers called laminae. The organization of these terminations ensure that different types of nerve fibers remain relatively independent, although there are some exceptions as we will see. These projections transmit information from the spinal cord to distinct pathways in the brain.

 

 

 

 

THE EVIDENCE

To my knowledge, these empirical observations are the strongest evidence that nociception and pain can be dissociated.

1. Pain perception does not always correspond to afferent nociceptor activity.

text

In a classic paper by LaMotte…

 

2. Nociceptor activity is detected below the threshold of conscious perception.

It is notable that the group that demonstrated a correlation between single nociceptor stimulation and subjective pain perception also showed a threshold of nociceptor stimulation required for “conscious detection” (Shady, Torebjork, and Ochoa, 1984)

3. Certain experimental conditions can change a nociceptor’s threshold for activation.

By definition, primary nociceptors specifically respond to noxious stimuli. However, many papers show that the response thresholds of nociceptors can be changed–meaning they are no longer activating to

Many papers have shown that the

4. Different patterns of brain activity mediate provoked (nociceptive) and unprovoked (spontaneous) chronic pain, suggesting the latter pain is independent of nociception.

In a 2018 paper on neural correlates of erythromelalgia pain recently published by Paul Geha and Steve Waxman,

5. We rely on imprecise measures of nociception.

Most noxious stimuli activate many nerve endings at once, so anything other than single-neuron experiments cannot determine the nociceptor/pain perception relationship.

 

Revisiting the Core Questions

 

1. Are nociception and pain the same thing?

We have reviewed clear evidence that differentiates nociception from pain perception.

 

2.Can nociception occur without pain perception?

 

3.Is nociception necessary and sufficient for pain perception?

Nociception is necessary for pain perception if (and only if) the lack of nociception guarantees (or brings about) the lack of pain.

This statement is false, given that pain can exist without nociception.

Nociception is sufficient for pain perception if (and only if) the occurrence of nociception ensures that pain will be perceived.

This statement is also false, given that nociception can occur without pain perception.

4.Can we feel pain without nociception?

Now What?