Nociception and the Pain System

In this wiki we will explore some of the neurobiology and neuroscience behind the human pain system. We will first look at how nociceptors relay the pain information to the brain and how this results in our perception and identification of pain. We will then proceed to a short computational tutorial meant to illustrate the wide range of stimuli intensities between a barely perceived stimulus and a painfully perceived stimulus. Finally, we will end with an exploration 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 amount of the stimuli 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 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] Upon activation 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] The high speed of depolarisation acts 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 pain system. It is only when the signal of depolarised nociceptors reaches the brain that pain is actually perceived.

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]

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 split 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 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.^[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 mechanic 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 illustrate an important facet of the pain system: even though the 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 act 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. The 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 joined 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 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:

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

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.

%Matlab comment
plot(x,y)

Figure 1: Human Hearing Range in W/cm².

%More colourful commentary
answer = 42;
sprintf('%.5f',answer)

ans =
    42

More normal words.

Last Section

More words in normal wiki style.

Fancy formula

$y=10log[\frac{w}{x^2}{]}^2$

Concluding Remarks

So long, and thanks for all the fish.

References

1. Fancy Text One
2. Fancy text two