Nociception and the Pain System

This wiki explores some of the neurobiology and neuroscience behind the human pain system. The first sections look at how nociceptors relay the pain information to the brain and how this results in the perception and identification of pain. Following this there is a short computational tutorial meant to illustrate the wide range of stimuli intensities between a barely perceived stimulus and a painfully perceived stimulus. The final section delves into the non-physical side of pain, focusing mainly on the cognitive factors that are intertwined with the pain system.

Introduction

The pain system is rather unique when compared to some of the other sensory systems we have at our disposal. While sensory systems such as vision and audition are extremely sensitive to small differences in the stimulus intensity detected, the pain system allows humans (and other animals) to perceive pain only when the amount of stimuli detected is sufficiently large to injure tissues or be toxic to the body. The perception of pain is mainly due to the activation of one of many specialised sensory neurons, better known as nociceptors, which can detect extreme amounts of temperature, pressure, or noxious chemical stimuli on the skin. Upon detecting these types of stimuli, nociceptors alert the brain by transducing the input from these stimuli into electrical signals that are received at somatosensory and cognitive cortical regions.

Physiology of Pain

Cutaneous (skin) nociceptors are found in the outside of the CNS at the peripheral sensory ganglia, where they act as excitatory neurons and utilise glutamate for neuro-transmission.^[1] In general nociceptive responses occur as a sub-second response to the presence of noxious stimuli, transmitting all-or-none action potentials only when the presence of a noxious stimulus is large enough in amplitude and duration.^[2] When nociceptors are activated, a depolarisation process occurs which causes the opening of ion channels permeable to sodium (Na⁺), calcium (Ca²⁺), and chloride (Cl^-) as well as the closing of potassium (K⁺) permeable channels. This amplifies current-induced voltage fluctuations in the nociceptor neuron and increases its membrane resistance. ^[1] This depolarisation process is extremely fast, which allows it to act as a fail-safe so that regardless of any slowing down of signal transmission or attenuation of signal intensity, the intensity of the stimulus will still be encoded and transmitted to the points of interest in the cortex, where pain will perceived only when the signal of the depolarised nociceptors reaches these cortical areas.

The perception of pain depends on three main factors: the frequency of action potentials transmitted by nociceptors, the speed of this transmission, and the temporal summation of synaptic signals. These three crucial factors tend to be modulated by the type of nociceptors that detects the pain stimuli, e.g., C-fiber or A-fiber nociceptors, as well as the local inhibitory and excitatory inter-neurons in the dorsal horn. Modulation of the pain signals allows the pain system as a whole to efficiently prioritise the most important pain stimulus at the instant it occurs, not only over other competing pain signals but also over other biological responses. ^[1]

Pathways of Nociception

The pathway of nociception transmission begins at the cell body of the neuron at the dorsal root ganglion or trigeminal ganglion from where the signal splits into two parts.^[1] The first part goes to the second-order neurons in the dorsal horn of the spinal cord or to the trigeminal subnucleus caudalis via the central axon. After the signal reaches one of these locations, it is then transferred to relay neurons, which propagate the signal into the medulla, mesencephalon, and the thalamus, from which the signal will then propagate even further into the somatosensory and anterior cingulate cortices.^[3] The signal that reaches the somatosensory cortices results in the sensory aspect of pain perception, e.g., the pain following a burn. The signal that reaches the anterior cingulate cortex, however, results in the affective and cognitive aspects of pain, which can lead pain perception to be a rather subjective sensory process particularly when compared to other more objective sensory systems, such as vision or audition.^[1] The second part of signal travels through the peripheral axons in order to innervate the skin at the location the stimulus was detected. This intricate separation of the signal transmission allows nociceptors to propagate the electric signals quickly and directly to the regions of interest, which reduces the probability that the signal is lost when travelling through the axonal pathways.

Nociceptor Types

C-fiber Nociceptors

C-fiber nociceptors are the most common type of nociceptor. These nociceptors have small unmyelinated axons surrounded by Schwann cells and are broadly distributed.^[2] Their peppered distribution scheme prevents them from localising a pain stimulus with high precision. In general, C-fiber nociceptors have conduction velocities of anywhere from 0.4 – 1.4 m/s. ^[1]

A-fiber Nociceptors

A-fiber nociceptors are specialised in sending initial fast-onset pain. As a result these nociceptors are myelinated and tend to be clustered together within a small area. Their tight clustering allows for precise localisation of a pain stimulus. A-fiber nociceptors have much faster conduction velocities than C-fiber nociceptors with velocities on the range of 5 – 30 m/s. A-fiber nociceptors are primarily responsive to heat and mechanical stimuli.^[1]

The Different Varieties of Nociceptive Responses

Temperature Nociception

Although nociceptive nerve endings are highly similar across animals, they are incredibly heterogeneous varying in both anatomical structure as well as in biochemical function.^[1] Temperature-based nociceptive responses are correlated with pain in humans throughout the spectrum of possible temperatures (i.e., from cold to hot); however, the responses at each side of the temperature spectrum are rather unique.^[4]

In the case of heat-related pain perception, upon the initial on-set of a stimulus just below the perceptual pain threshold for heat (approx. 40°C to 45°C), A-fibers modulate the onset of pain via a quick activation of the nociceptive nerve endings signalling the brain to take evasive manoeuvres.^[1] For example, if a hot candle is placed on a person's arm, A-fibers would quickly activate and send a message to the somatosensory brain regions ordering the movement of the exposed body region away from the candle. On the other hand, the activation of C-fibers will only occur after the nerve endings have been exposed to the noxious temperature for a long time, at which time pain perception will signal the presence of an injury.^[5]

In contrast to the perception of heat-related pain, the perception of cold-related pain tends to be felt much more linearly (particularly in the range of 20°C to 0°C), although the actual threshold of cold-related pain is more ambiguous varying widely from person to person and from animal to animal.^[1] For example, while in mice the fibres responsible for non-noxious cold transduction have small diameters (i.e., they are similar to C-fibers), in humans it is the A-fibers alone which control and suppress non-noxious cold response in humans.^[5] The difference between responses to hot and cold stimuli illustrates an important facet of the pain system: even though sensory perception covers a wide range of stimuli, the way a particular stimulus intensity is encoded varies greatly based on both the characteristics of the stimulus as well as where on the body the stimulus acts on.

Mechanical Nociception

Since research into the perception of noxious mechanical stimuli is in its early stages, not much is known about the exact mechanics that cause animals to feel mechanically-graded pain. Research into the biology of mechanical nociceptor activity has shown that nociceptor potential is graded at an ion channel level. For example, onset of a high pressure mechanical stimulus initiates ion fluxes of inward Na⁺, K⁺, and Ca²⁺ currents which grade the nociceptor potential based on stimulus intensity and frequency.^[6] The manner in which this gradation of the nociceptor potential is actually perceived, however, is not yet understood especially in light of studies that have found that as opposed to the high correlation observed between temperature-related nociceptive responses and pain perception, human pain perception in response to varying degrees of noxious mechanical stimulation is not greatly correlated.^[7] This large difference between temperature and mechanical nociception illustrates once again the diversity of nociceptive responses.

Chemical Nociception

The nociception of noxious chemical stimuli is generally inter-related with that of temperature and, as such, these two share a number of similarities. Exposure to a chemical stimuli (such as the capsaicin found in hot peppers or mustard oil) lowers the threshold of C-fiber activation, which ultimately results in the perception of pain.^[5] On the onset of C-fiber activation, the pain system adapts the exposed area by creating a large zone of flare (e.g., swelling or reddening), which increases responsiveness in this area to both noxious (hyperalgesia) and non-noxious (allodynia) stimuli which might interact with the area.^[7] This adaptation is propagated in a joint effort between the central and the peripheral nociception pathways.^[7] This complicated process begins by the central pathway signals propagating responses to the peripheral pathways so that these can release peptides to cause autocrine or paracrine effects on the region of interest ultimately contributing to the inflammatory defensive response.^[1] The perception of pain in the presence of this inflammatory response is suggested to be caused by the continuing activation of the nociceptors at the site of interest, even if the region is not exposed to the noxious chemical stimuli any more.^[1]

Pain Thresholds

Humans are exposed to various kinds of stimuli each with a corresponding intensity. As mentioned above although some stimuli intensities are harmless, others can be quite painful. We will illustrate this through a short MATLAB computational tutorial on the perception of pain in the auditory system.

Sound intensity is generally measured in decibels (dB) a ratio of an intensity relative to a base value (in our case we will use the threshold for hearing). To compute the intensity in dB, I(dB), of a sound based on the sound's intensity in Watts/cm² we can use the following equation:

$I(dB)=10lo{g}_{10}\left[\frac{I}{I_0}\right]$

where I₀ is the human threshold for hearing at 10^-16 Watts/cm², and I is the intensity of a sound we might hear.^[10] Using this equation we can transform back and forth between the intensity of a stimulus in Watts/cm² to dB.

Using a wide spectrum of intensities, we will use the sound intensity equation to compute a range of intensities within the human-audible range. We will use some of the common sound intensities found at http://physics.info/intensity/. Depending on the intensities used, these numbers can vary a bit.

ihearing = 10^-16;

intensity = ihearing:200;
intensitydb = 10*log10(intensity/ihearing);

dbhearing  = 0;
dbconversation = 60;
dbearprotect = 80;
dbrock = 110;
dbpain = 130;
dbrocket  = 180;
commondb = [dbhearing dbconversation dbearprotect dbrock dbpain dbrocket];

Now using a little bit of algebra we can get the original intensities (in Watts/cm²) from our intensities in decibels.

commondb10 = 10.^commondb;
ncommon = nthroot(commondb10,10);

commonintensities = ihearing.*ncommon;
sprintf('%.5f ',commonintensities)

ans =

     0.00000 0.00000 0.00000 0.00001 0.00100 100.00000 

As a sanity check, we can re-compute the original intensities in decibels.

10*log10(commonintensities./ihearing)

ans =

     0    60    80   110   130   180

Since everything checks out, let's plot our sound intensities.

mini = min(intensity)-10;
maxi = max(intensity)+50;
minidb = min(intensitydb)-50;
maxidb = max(intensitydb)+50;

plot(intensity,intensitydb);
axis([mini maxi minidb maxidb]);
hold on;

plot(commonintensities(1:2),commondb(1:2),'ko','MarkerFaceColor',[0 1 0]);
text(commonintensities(1)+2,commondb(1),'Hearing Threshold');
text(commonintensities(2)+2,commondb(2),'Casual Conversation');

plot(commonintensities(3:4),commondb(3:4),'ko','MarkerFaceColor',[1 .5 0]);
text(commonintensities(3)+2,commondb(3),'Ear Protection Required for Prolonged Work');
text(commonintensities(4)+2,commondb(4),'Rock Concert');

plot(commonintensities(5:6),commondb(5:6),'ko','MarkerFaceColor',[1 0 0]);
text(commonintensities(5)+2,commondb(5),'Threshold of Pain');
text(commonintensities(6),commondb(6)-5,'Rocket Launch');

title('Range of Human Hearing');
xlabel('Intensity in Watts/cm^2');
ylabel('Intensity in dB');
hold off;

Figure 1: Human Hearing Range in W/cm².

Since the sounds we hear are actually just fluctuations of pressure in the air, we can measure sound intensity in pressure units as well. On Earth the average atmospheric pressure at average sea level is 1 atmosphere = 1 Newton/m². The human threshold of hearing, however, is 2*10^-5 N/m². To find the intensity (dB) at a given pressure we can use the following equation:^[10]

$I(dB)=10lo{g}_{10}\left[\frac{P^2}{P_0^2}\right]=20lo{g}_{10}\left[\frac{P}{P_0}\right]$

where P is the pressure of a sound heard and P₀ is the human threshold for hearing.

Let's recompute our intensities using pressure in atm instead of intensity in W/m². The computations are essentially the same but do notice that our intensities in decibels are now a function of 20*log₁₀(P/P₀); therefore, when solving for the relative intensities, our units will be pressures in N/m².

phearing = 2*10^-5;
pressure = phearing:20000;
pressureintensdb = 20*log10(pressure/phearing);

commondb = [dbhearing dbconversation dbearprotect dbrock dbpain dbrocket];
commondb10 = 10.^commondb;
ncommonpressure = nthroot(commondb10,20);

commonpressures = phearing.*ncommonpressure;
sprintf('%.3f ',commonpressures)

ans =

     0.000 0.020 0.200 6.325 63.246 20000.000

Checking our work, we find the original intensities match.

ans =

     0    60    80   110   130   180

mini = min(intensity)-10;
maxi = max(intensity)+50;
minidb = min(intensitydb)-50;
maxidb = max(intensitydb)+50;

plot(intensity,intensitydb);
axis([mini maxi minidb maxidb]);
hold on;

plot(commonintensities(1:2),commondb(1:2),'ko','MarkerFaceColor',[0 1 0]);
text(commonintensities(1)+2,commondb(1),'Hearing Threshold');
text(commonintensities(2)+2,commondb(2),'Casual Conversation');

plot(commonintensities(3:4),commondb(3:4),'ko','MarkerFaceColor',[1 .5 0]);
text(commonintensities(3)+2,commondb(3),'Ear Protection Required for Prolonged Work');
text(commonintensities(4)+2,commondb(4),'Rock Concert');

plot(commonintensities(5:6),commondb(5:6),'ko','MarkerFaceColor',[1 0 0]);
text(commonintensities(5)+2,commondb(5),'Threshold of Pain');
text(commonintensities(6),commondb(6)-5,'Rocket Launch');

title('Range of Human Hearing');
xlabel('Intensity in Watts/cm^2');
ylabel('Intensity in dB');
hold off;

Figure 2: Human Hearing Range in N/m².

The wide range of sound pressures and intensities illustrates that, although humans can perceive small changes in stimulus intensities, there are certain stimulus intensities which can be harmful to the human body. However, it is important to note the large distance between our hearing threshold (0 dB) and our threshold for pain (130 dB).

The same kind of computations can be done in other modalities, although since pain perception in areas such as temperature are dependent on the type of temperature exposure, e.g., hot climate vs. holding a hot ceramic plate vs. holding a hot aluminium plate, computing these curves requires more rigorous experimental testing. However, there are similarities between the modalities. For example, pain thresholds due to material temperature differences also seem to follow a roughly logarithmic curve.^[12]

Cognition and Nociception

Although the study of pain is mainly focused on the the physiological experience of pain, i.e., how do the body and the brain work together to detect and react to physical pain, human beings can also experience pain as a result of cognitive and emotional factors. The main difference between the experience of physically caused and cognitively caused pain is in the brain centres at which each of these is processed. While physical pain is processed at the somatosensory cortices, cognitive pain (i.e., non-physical pain) is processed primarily at the anterior cingulate cortex (ACC) with joint activation at the insula, thalamus, and pre-frontal cortex. ^[8][9] The processing of pain at these regions has profound implications in the experience of cognitive pain perception as it makes cognitively-caused pain controllable and alarmingly subjective.

Studies into the underlying tenets of cognitive pain have found that the experience of cognitive pain is highly correlated with the anticipation of experiencing future pain.^[9] As a person ruminates more and more over a future experience of pain, the actual experience of pain once a noxious stimulus is presented increases considerably.^[9] In other words, as the duration of thinking about future pain increases so does the perceived magnitude of the pain stimulus increase once it is actually present. Furthermore, the magnitude of a pain stimulus is not only directly proportional to the duration of the pain anticipation period but also to the believed magnitude of future pain. That is, if person believes that the degree of painfulness of a future noxious stimulus will be high, then the experience of the noxious stimulus will be more painful than if the person had believed that the stimulus would not be very painful.^[9] However, this expectation of a future painful stimulus is not purely cognitive. The expectation and anticipation of a painful stimulus is positively correlated with activation in the ACC, where the greater the believed level of a future painful stimulus, the greater the activation at the ACC will be. The activation at the ACC is also accompanied by activation in the PFC, thalamus, insula, and cerebellum.^[9]

Due to cognitive nature of the perceived pain, human beings have been found to be able to control the degree of perceived pain by mentally training themselves to do so.^[8] As mentioned above one main factor used in controlling pain perception is the reduction of the expected magnitude of a future painful stimulus or the reduction of the expectation period which precedes a painful stimulus.^[9] However, on the onset of a painful stimulus there exist three additional methods that have been found to reduce the degree of pain perceived. Given the ability to observe the cortical activation by means of a real-time fMRI (rtfMRI) measure, the degree of a pain produced by a noxious stimulus can be reduced by: shifiting attention from the location of the painful stimulus to another side of the body, by convincing oneself that the pain felt is a neutral sensory stimulus rather than a highly painful one (e.g., slightly warm plate instead of scorching hot plate), and/or by perceiving the stimulus (although still painful) to be of low pain intensity.^[8] Through the use of these techniques in the presence of an rtfMRI measurement, the human perception of pain has been observed to be significantly less than when these techniques are not used.^[8] Furthermore, these voluntary and conscious pain modulation techniques have been found to be effective not only in cases of acute or short-term pain but also in chronic pain. However, the same effects have not been observed in the absence of an rtfMRI measurement, which provides feedback to the person experiencing the noxious stimulus as to the degree of activation within pain centres in the brain (e.g., ACC).^[8] Due to this, these early findings have questionable validity when it comes to real-life applications particularly as the pain management produced by these rtfMRI methods may simply be a result of attention shifts away from the painful stimulus and into watching the rtfMRI response.

Conclusion

The pain perception is a result of an intricate interaction between specialised sensory neurons and cortical somatosensory areas as well as the anterior cingulate cortex. Through this interaction the human body is able to perceive when a noxious stimulus intensity is present and to respond appropriately, physiologically and cognitively, to the situation. This response may range from physically evading the stimulus to controlling the perception of pain, although the degree to which this latter technique is effective is not well understood at the moment.

References

1. Dubin, A. E., & Patapoutian, A. (2010). Nociceptors: the sensors of the pain pathway. The Journal of clinical investigation, 120 (11), 3760.
2. Woolf CJ, Ma Q. Nociceptors—noxious stimulus detectors. Neuron. 2007;55(3):353–364.
3. Millan MJ. The induction of pain: an integrative review. Prog Neurobiol. 1999;57(1):1–164.
4. Van Hees J, Gybels J. C nociceptor activity in human nerve during painful and non painful skin stimulation. J Neurol Neurosurg Psychiatry. 1981;44(7):600–607.
5. Raja SN, Meyer RA, Campbell JN. Peripheral mechanisms of somatic pain. Anesthesiology.1988;68(4):571–590.
6. Giordano, J. (2005). The neurobiology of nociceptive and anti-nociceptive systems. Pain Physician, 8(3), 277-90.
7. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10(9):895–926.
8. DeCharms, R. C., Maeda, F., Glover, G. H., Ludlow, D., Pauly, J. M., Soneji, D., ... & Mackey, S. C. (2005). Control over brain activation and pain learned by using real-time functional MRI. Proceedings of the National Academy of Sciences of the United States of America, 102(51), 18626-18631.
9. Koyama, T., McHaffie, J. G., Laurienti, P. J., & Coghill, R. C. (2005). The subjective experience of pain: where expectations become reality. Proceedings of the National Academy of Sciences of the United States of America, 102(36), 12950-12955.
10. Nave, R. Retrieved from http://hyperphysics.phy-astr.gsu.edu/Hbase/sound/intens.html
11. Elert, G. Retrieved from http://physics.info/intensity/
12. Stoll, A. M., Chianta, M. A., & Piergallini, J. R. (1982). Prediction of threshold pain skin temperature from thermal properties of materials in contact. Aviation, space, and environmental medicine, 53(12), 1220.