An Introduction to Pain: A sixth sense?

Classically, human beings were thought to possess 5 senses: smell, taste, hearing, sight and touch. But advances in our understanding of the latter make it clear that we can spin-off the sense of touch into a number of subcategories. Discriminative touch is the sense that allows us to feel the texture of objects. Proprioception is the sense of limb position and movement in space. And finally nociception is the sense that allows us to perceive pain when we are presented with a noxious (painful) stimulus.

Older theories suggested that pain was simply an intense activation of the sense of touch. This idea, whose main proponent was German neurologist Wilhelm Erb, was known as "intensity theory". However, this became untenable upon the discovery of small calibre, unmyelinated peripheral nerve fibres that are specifically activated by painful stimuli. These fibres, that were first observed by the English physiologist Charles Sherrington, are called C fibre nociceptors. With the advent of molecular biology, it became clear that unmyelinated C fibre nociceptors were a highly conserved means of pain sensing across the animal kingdom, from complex mammals such as humans, to simpler organisms such as the fruit fly.

The discovery of C fibres revived the "specificity theory", an older idea originally proposed by philosophers Avicenna and Descartes. This holds that pain is a special class of signals detected by and passed along cells that are uniquely activated by noxious stimulation. In other words this theory suggests that the sense of pain is physiologically segregated from the other senses, at every stage of the ascending pathways, from the receptors in the periphery to the brain.

While there is quite strong evidence for some degree of modality segregation in peripheral nerve fibres, the distinction seems to be more blurred at the central level. The existence of cells in the spinal cord that integrate inputs from both noxious and innocuous peripheral fibres suggests that the transition from peripheral to central nociception is likely to be more complicated than the specificity theory would suggest.

Descartian conception of pain

Descartes’ prescient conception of the pain

pathway: “If for example fire

(A) comes near the foot (B), the minute

particles of this fire, which as you know

move with great velocity, have the

power to set in motion the spot of the

skin of the foot which they touch, and

by this means pulling upon the delicate

thread (c) which is attached to the

spot of the skin, they open up at the

same instant the pore (d, e, F) against

which the delicate thread ends, just as

by pulling at one end of a rope makes

to strike at the same instant a bell

which hangs at the other end.”

 

The perception of pain

Pain is a physiological signal that an organism uses to avoid physical harm. 

Different types of painful stimuli are sensed by a diverse range of nociceptor terminals found in the skin, muscle and viscera (see Nociceptors: the starting blocks below). Every time a noxious stimulus depolarises a nociceptor terminal, a series of action potentials are generated. These travel along the pain fibre and towards the spinal cord, where they synapse with spinal cord projection neurons (see The Spinal Cord: the relay below). This synapse in the spinal cord is a key stage at which transformation and modulation of pain signals arising in the periphery can occur, before they proceed on to the brain.

Pain consists of both a somatosensory component (nociception) and a psychological, affective component. While nociception refers to the neural activity in the peripheral and central nervous system associated with a potentially painful stimulus, pain encompasses both this and the central nervous system-generated emotional and autonomic response to nociception. It appears that these component parts of pain are processed in separate, discrete areas of the brain (see The Brain: the finishing line below). The relationship between nociceptive input and the pain experienced by an individual is often complex. While nociception is usually the cause of pain, it is neither necessary nor sufficient and is very often not linearly related to the resulting subjective pain experience. This is partially due to the presence of a feedback loop between the brain and spinal cord that can alter the extent to which pain signals are allowed through the spinal cord (see A Spino-bulbo-spinal loop: the brain's feedback to the spinal cord)

In theory, analgesics can work at any of the points described above. Local anaesthetics work on the peripheral fibres themselves; epidural analgesia during labour inhibits transmission at the spinal cord and the drugs used to treat pain following nerve injury, many of which were originally antidepressants, act on the brain.

Nociceptors: the starting blocks

A nociceptor is a peripheral nerve fibre that is activated by potentially damaging environmental stimuli.

These environmental stimuli can be: mechanical (e.g. hitting your thumb with a hammer), thermal (e.g. burning your finger with boiling water) or chemical (e.g. lemon juice in a cut). Some nociceptors respond to only one modality of stimulus  (e.g. mechanical-specific). Others can be activated by a variety of stimuli (polymodal nociceptors). Some nociceptors are normally not responsive to environmental stimuli, but will become responsive following tissue damage (silent nociceptors). In contrast to innocuous touch receptors, which tend to have specialised sensory organs at their endings in the skin (e.g. Pacinian Corpuscles), nociceptors tend to simply have unmyelinated free nerve endings in their termination sites in skin, muscle and viscera.

Nociceptors can also be activated under different circumstances, such as inflammation, deep musculoskeletal damage, childbirth or neuropathies.

Peripheral Nerve Fibres



Properties of peripheral nerve fibre

Peripheral nerve fibres can be subdivided into Aβ, Aδ and C fibre classes. 

Electrophysiology studies, as well as histological and molecular analysis of peripheral nerve axons and cell bodies in the dorsal root ganglion (DRG) reveal a number of distinctive properties for each fibre class. They can be distinguished based on their physical properties (e.g. calibre, myelination); functional properties (e.g. conduction velocity, adaptation, modality-specificity); and biochemical properties (e.g. growth factor dependency, expression of neuropeptides and ion channels).

Aβ fibres: high conduction velocity myelinated axons. They can be rapidly or slowly adapting. Although these are mainly detectors of low threshold discriminative touch, it is important to remember that they do also fire in response to noxious stimuli and can therefore contribute to nociception. In some experimental pain models, Aβ fibre stimulation to the spinal cord is perceived as painful, resulting in hypersensitivity to mechanical stimulation (tactile allodynia).

Aβ fibres release glutamate at the synapse. They respond to the neurotrophin ganglioside GM1 and express the structural protein Neurofilament-200. They do not usually express neuropeptide contransmitters like smaller fibres do. However, one possible mechanism of hyperexcitability after injury is de novo expression of neuropeptides in large Aβ fibres.

Aδ fibres: average conduction velocity myelinated axons.

Aδ fibres relay information coming from mechanical nociceptors and thermal nociceptos. 

Certain ion channels, such as the potassium channel family KCNQ, may be enriched on Aδ fibres. Their growth factor dependency and neuropeptide expression are broadly similar to that of C fibres.

C fibres: slow conduction velocity, thin unmyelinated axons.

C fibres relay information coming from polymodal nociceptors, which are sensitive to mechanical, thermal and chemical high-intensity stimulation. 

These fibres are so small they are found in much greater density than A fibres. This is partly why C fibre stimulation evokes a higher firing rate in the spinal cord than A fibre stimulation does, even though individual myelinated fibres are able to fire at a higher frequency than individual C fibres. 

C fibres are the primary chemosensors among nociceptors, detecting endogenous proinflammatory factors like cytokines and bradykinin as well as environmental irritants. In many cases, this detection occurs via Transient Receptor Potential (TRP) channels. These are ligand-gated ion channels. They allow the detection of mustard oil (TRPA1), capsaicin/chilli extract (TRPV1) and menthol (TRPM8), as well as many other chemicals.

How does it feel when you stimulate one class of fibres selectively?



Defined Aβ, Aδ and C fibre populations can be specifically activated using transcutaneous electrical stimulation, intraepidermal electrical stimulation or laser stimulation respectively.

Each fibre population produces distinctive sensations – shocking through Aβ fibres, tingling/pricking through Aδ fibres and pricking/burning through C fibres. 

The A fibres are the fast acting ones and they are responsible for the onset of the first sharp pain that you feel when you hurt yourself. This is immediately followed by a slower, more prolongued burning pain which is transmitted by the slower C fibres.

Neurotransmitters used by nociceptors

Most primary afferents use glutamate as a fast excitatory neurotransmitter, which produces rapid onset and brief excitatory post-synaptic potentials (EPSPs). Others also use ATP.

A distinctive property of small fibres is the expression of neuropeptide cotransmitters like the calcitonin gene-related peptide (CGRP) and substance P, which are released following high frequency stimulation. These transmitters trigger a longer latency, longer duration EPSPs in projection neurons and also act in a paracrine fashion between primary afferent terminals in the spinal cord.

Interestingly, in addition to afferent transmission that senses peripheral stimuli and conveys action potentials to the spinal cord, C fibres also release neuropeptides from their peripheral endings in skin and muscle when stimulated at a high frequency.

Efferent C fibre transmission produces vasodilatation (redness/flare around the site of stimulation or injury), plasma extravasation (a weal) and mast cell degranulation in target tissues, a process known as neurogenic inflammation or the axon reflex. These effects occur via actions of neuropeptides on vascular smooth muscle, immune cells and epidermal cells.

Gain of function in neuropeptidergic transmission is especially clear in Complex Regional Pain Syndrome, a condition that often follows injury to bones where pathological overexpression of neuropeptides produces painful autonomic abnormalities in the skin.

The Spinal Cord: the relay

Like the brain, the spinal cord is divided into grey matter (containing cell bodies, grey in the schematic below) and white matter (containing axon tracts, demarkated by a dotted line below). In the grey matter, cells are arranged in layers called laminae. The dorsal horn laminae I-VI of the spinal cord receive and process sensory inputs, while the ventral horn Laminae VII-IX contain motor outputs (for example, the motor outputs of monosynaptic reflexes).

In laminae I and II, the superficial dorsal horn, nociceptive specific (NS) cells receive direct C and A fibre inputs. In laminae IV and V, wide-dynamic range neurons (WDR) receive convergent direct and indirect (via interneurone) inputs from all fibre types. Inhibitory interneurons are also present throughout the dorsal horn (they are especially common in the Substantia Gelatinosa region in Lamina II)

All laminae also receive descending fibres from forebrain and midbrain sites that can be either excitatory or inhibitory – these give the brain the capacity to modulate the passage of nociceptive information passing through the spinal cord in response to changes in context.

Thus the spinal cord processing of pain can effectively be reduced in conception to 5 elements:

  • Primary afferent inputs (A and C fibres)
  • Second order neurons (projecting to the brain or within the cord)
  • Interneurons (inhibitory or excitatory)
  • Motor outputs (from the ventral horn)
  • Descending controls (excitatory or inhibitory)

 

The neurotransmitters used in the spinal cord dorsal horn are:

  • glutamate, purinergic and peptidergic cotransmitters (released by primary afferents and excitatory interneurons)
  • GABA and glycine (released by inhibitory interneurons)
  • noradrenaline and serotonin (released from the terminals of descending modulatory fibres arising in the midbrain). 

    Spinal cord anatomy

    note laminae in grey matter

    The Brain: the finishing line

    Following the transformations of peripheral nociceptive information undertaken by convergent spinal neurons and the network of the dorsal horn, spinal projection neurons cross the midline to enter ascending tracts conveying nociceptive information to the brain. At this stage, inputs will enter consciousness and be perceived as pain.

    In parallel, another process, sometimes referred to as a spino-bulbo-spinal loop, will also take place, whereby ascending inputs entering the amygdala, hypothalamus and medulla trigger the engagement of neurons with cell bodies in these sites, which project descending fibres back to the spinal cord.

    The modulatory effects of these fibres are a key determinant of the extent to which pain entering the nervous system from the periphery actually reaches conscious perception. Inter-individual differences in descending fibre engagement may even contribute to the likelihood of an individual experiencing chronic, pathological pain following the establishment of a given disease state or injury.

    The functional roles of nuclei and tracts in these pathways have classically been elucidated using techniques including electrophysiology, neuronal tracers, surgical section, accidental traumatic damage, electrical or chemical ablation, electrical stimulation, cold block and local anaesthetic block. Recently, electroencephalogram, positron emission tomography and functional magnetic resonance imaging have also proved useful. 

    Pain activates a wide range of brain areas including primary and secondary somatosensory, insular, cingulate and prefrontal cortices, as well as the thalamus. It may be the case that the subjective experience of pain cannot be localised to specific brain regions in the way that, say, vision can be. Rather, it may be the result of highly temporally structured activity distributed around many areas of the brain. In contrast, the midbrain and brainstem areas that are activated (subconsciously) by painful stimuli are relatively well characterised.

    Ascending and descending pathways

    The ascending and descending projections linking the spinal cord, midbrain and higher centres of the

    Ascending and descending projections link the spinal cord, midbrain and higher centres of the brain.

    The ascending tracts can be defined according to where they terminate in the brain. For pain transmission, the two main tracts are:

    Spinothalamic (terminating in the thalamus, highlighted in blue above) and spinobulbar (terminating in midbrain and hindbrain pain-modulating sites, highlighted in red above). The spinobulbar projections could also be subdivided into the spinomesencephalic (terminating in midbrain) and spinoreticular (terminating in brainstem) tracts.

    There are also other tracts such as the spinohypothalamic (terminating in the thalamus - for simplicity this schematic omits this tract, although it does play a role in nociception).

    Descending fibres, which modulate pain signals as they pass through the spinal cord, are shown above in green.

     

    Focus on two ascending pathways

    The spinothalamic tract

    The spinothalamic tract (STT) conveys the discriminative/localisation aspects of pain by projecting to the thalamus.

    Selective stimulation of STT elicits pain and burning sensations, while selective interruption of the STT disrupts these modalities. 

    After synapsing in the thalamus, projections reach the sensorimotor cortex, insular cortex and the anterior cingulate, which integrate thalamic and other inputs to generate the percept of pain, localised to a specific region of the body.

    The spinobulbar tract

    The spinobulbar tract (SB) projects to the amygdala and hypothalamus via the parabrachial nucleus to convey the affective/intensity aspects of pain.

    The spinobulbar pathway is able to recruit descending controls via the periaqueductal grey, pontine locus coeruleus and rostroventromedial medulla. These monoaminergic modulatory controls can promote or inhibit the passage of nociceptive information passing through the spinal cord. 

    This endogenous pain control process is described in greater detail below.

    A Spino-bulbo-spinal loop: the brain's feedback to the spinal cord

    Spinobulbar tract projections terminate in areas subserving visceral and autonomic regulation and affective state.

    Periaqueductal Grey

    Before reaching their ultimate projection sites in the amygdala and hypothalamus, which have clear affective and autonomic regulatory roles, many SB projections pass via the periaqueductal grey (PAG). The PAG is a site at which both ascending nociceptive and descending modulatory fibres converge. Electrical stimulation of some sites in the PAG can elicit analgesia. This analgesia occurs via descending projections from the PAG to the spinal cord that travel via the rostroventromedial medulla (RVM) and the LC.

    Locus Coeruleus

    For example, the pontine Locus Coeruleus (LC) contains monoaminergic cells that are integration sites for cardiorespiratory and homeostatic function. Pre-autonomic bulbospinal outputs from the LC can modulate peripheral autonomic activity, allowing interaction between pain, arousal and behavioural states. Most significantly, noradrenergic descending projections arising in the LC can modulate nociceptive throughput in the spinal cord by releasing noradrenaline in the spinal cord.

    Rostroventromedial Medulla

    Electrical stimulation or microinjection of excitatory amino acids into the RVM produces analgesia and inhibits spinal dorsal horn neuronal responses to noxious stimulation.

    The pain-modulating neurons in the RVM are classified as ON, OFF or NEUTRAL cells according to their tendency to increase, decrease or maintain firing during noxious stimulation. These cells often have whole body receptive fields and project to both the superficial and deep laminae of the dorsal horn. The balance of activity in the RVM is likely to be a large determinant of an organism’s response to a potentially noxious stimulus. The balance of RVM net output can be shifted to ‘inhibitory’ (antinociceptive) pharmacologically, most notably by exogenous or endogenous opioids. 

    Descending Fibres

    Serotonergic and noradrenergic descending fibres arising from the RVM or LC project back down from the brain to contact interneurons, primary afferents and projection neurons in the spinal cord. The effect of monoamines released from descending fibre modulators will largely depend upon the receptor subtype expressed on a given spinal cell type. For example, presynaptic 2-adrenoceptors are inhibitory when activated, while postsynaptic 1 adrenoceptors are excitatory.

    Depletion of spinal 5-HT attenuates the pain state induced following spinal nerve ligation, suggesting that spinal serotonin can function to maintain painful hypersensitivity.

    Contrastingly, consider experiments where animals receive a nerve injury intended to produce neuropathic pain-like hypersensitivity. Not all animals actually develop the hypersensitivity. The non-responders to injury appear to be protected from the pain state by higher levels of activity in their descending noradrenergic controls, as blockade of these controls using RVM lidocaine or spinal alpha2 adrenoceptor antagonists is sufficient to induce hypersensitivity in these animals.

    Plasticity of noradrenaline and serotonin receptor expression and function are often seen in experimental pain states, and it is likely that many antidepressant analgesics act by modulating descending controls.

    In summary, painful stimuli are first sensed by peripheral fibres and projected to the brain via the spinal cord. Then descending controls provide a mechanism for the brain to alter the extent to which these painful inputs are allowed to pass through the spinal cord, forming a feedback loop.

    How Can Pain Sensing Go Wrong?

    Pain upon tissue damage not only tells an organism to avoid potentially harmful stimuli, but also promotes immobilization and protection of a damaged tissue, so as to promote healing. However, this evolutionary function of pain can be temporarily or permanently disrupted by loss of function, gain of function or out-of-place function in pain signalling.

    An example of temporary loss of function is when the subjective experience of pain is altered in extreme situations. For example, in the heat of battle, soldiers may disregard minor injuries that would otherwise be extremely painful. This is probably the result of the effects of adrenaline, together with state-dependent engagement of descending fibres from the brainstem which modulate the passage of painful stimuli through the spinal cord.

    Permanent loss of function is seen in patients with the autosomal genetic condition congenital insensitivity to pain. People with this condition are prone to accidental burns, oral lesions and other physical injuries, especially during early life. This condition is primarily caused by a loss-of-function mutation in a voltage-gated sodium channel found in pain-sensitive nerve fibres.

    Gain of function results in the opposite experience of pain and can lead to a pathological overactivity of pain sensing fibres. An example of permanent gain of function is in patients suffering from erthyromelalgia, a disease caused by a different mutation in the voltage-gated sodium channel. This neurovascular disorder is characterised by peripheral erythema, swelling, deep aching and burning pain.

    Gain of function in pain experience is not only secondary to mutations in ion channels, and can occur in a wide range of other scenarios. The chilli plant produces a compound called capsaicin that can temporarily activate heat-pain sensing nerve fibres in the absence of an actual change in temperature (see A Human Experimental Pain Model: capsaicin injection below). In addition to capsaicin, various phytochemicals and animal venoms interact with the pain-sensing nervous system, often acting via ion channels.

    Out-of-place (or ectopic) pain sensation is seen in conditions such as phantom limb pain. Here, pain may be perceived in an amputated limb, despite the pain sensing fibres for that limb no longer being in place. This pain is hence generated centrally, and reflects maladaptive plasticity in area of the brain that formerly received inputs from the now amputated limb.

    A less drastic form of ectopic activity is seen following injury to peripheral nerve. In some cases, these patients experience a qualitatively distinct pain marked by features such as tingling and 'electric shocks', often occuring in spontaneously bursts of pain not linked to stimulation. These types of pain are proposed to be linked to bursts of spontaneous electrical activity with distinctive 'mulitiple spike' features in peripheral nerve.

    A human experimental pain model: capsaicin injection

    The capsaicin injection model

    4 variations of the capsaicin-chilli extract injection model

    A: the standard model. After injection, an area of flare develops close to the injection site (redness, swelling). This is accompanied by an area of heat hyperalgesia, and a larger area of mechanical hyperalgesia.

    B: local anaesthetic block of the nerve at elbow level prevents the development of hypersensitivity, though flare still occurs. Hence flare requires only excitation of the peripheral part of the nerve nerve, while hyperalgesia requires inputs to reach the spinal cord.

    C: insertion of a microelectrode into the nerve allows the selective stimulation of peripheral nerve fibres with A fibre intensity. This causes a sensation of innocuous touch.

    D: following capsacin injection, the previously innocuous A fibre stimulation is perceived as noxious. This suggests that the capsaicin injection triggers changes in the way normally non-painful inputs are processed at the spinal level.

    What do these experiments show us?

    While inflammation and pain fibre activating chemicals like capsaicin act first on primary affrent fibres, the long lasting central sensitization they can produce is a result of changes in the spinal cord, rather than changes in the originally activated peripheral fibres.

    Chronic Pain States

    The most clinically significant and common gains of function in pain occur in chronic pain states, particularly following damage to the peripheral or central nervous system (PNS or CNS). For example, in diabetic patients with peripheral neuropathy, a common symptom is loss of fine touch and thermal sensitivity (hypoaesthesia). This is often combined with pain produced by usually innocuous stimuli (allodynia), amplified intensity of response to painful stimuli (hyperalgesia) as well as spontaneous or qualitatively altered pain and somatosensation (paroxysmal pain, paraesthesias). These phenomena occur in a variety of other instances of nerve lesion such as post-herpetic neuralgia and complex regional pain syndrome.

    Equally, following injury of the CNS such as stroke or spinal cord trauma, the same combination of loss and gain of function resulting in persistent pain is seen. Even in disorders with no clear neuronal lesion, such as irritable bowel syndrome, pain in response to previously innocuous physiological events can occur. Conditions that feature tissue degeneration or inflammation, such as osteo- or rheumatoid arthritis, can also sensitize and activate peripheral and central nociceptive elements.

    Acute, neuropathic, inflammatory and chronic pain states possess distinct pharmacological sensitivities. An analgesic that is able to reduce acute pain may be unable to reduce neuropathic pain. Often drugs originally developed as antidepressants or anticonvulsants are effective in neuropathic pain, the significance of which is becoming clearer as the mechanism of action of these drugs in neuropathic pain states is studied. Analgesia for chronic conditions is also less successful because it carries a greater risk of treatment-associated adverse events.

    Where pain is experienced constantly in association with a chronic condition that is unlikely to resolve naturally, such as osteoarthritis or post-herpetic neuralgia, it loses its initial injury-avoidance cue role and becomes a pathological source of disability and distress. Hence the clear clinical need for more effective, better tolerated analgesics to relieve the suffering of patients with chronic pain and prevent the reduced quality of life that comes with disabling pain. This is the ultimate aim of pain research.

    Bibliography

    • McMahon, S., Koltzenburg, M. (2005). Wall and Melzack's Textbook of Pain. 5th Edition. Elsevier Churchill Livingstone.
    • Rang, H.P., Dale, M.M., Ritter, J.M (2012). "Pharmacology". 6th edition. Edinburgh: Elsevier Churchill Livingstone.
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