Anatomy of Pain

This description began as a paper presented at the Ontario Inter-Urban Pain Conference, held in Waterloo 29/11/1996, by Don Ranney, MD, FRCS, Founder and at that time Head of the School of Anatomy, University of Waterloo; Consultant, Orthopaedic Medicine and President, Disability Assessment Services, Inc.

This was tho opening presentation at a conference on Mind-Body Pain and has been updated many times since then as new information was discovered.

What is Pain?

Four centuries ago Descarte described pain in terms of an alarm bell ringing in a bell tower. From this came the concept that there can be false alarms and we have therefore come to distinguish "psychogenic pain" from "real pain". This is now known to be a false distinction, but still we hear today the concept of hurt being not the same thing as harm, with the implication that much that hurts may be ignored. The International Association for the Study of Pain has published the following definition of pain which reflects what has been learned about pain in the last four centuries, and primarily in the past half century.

Pain is "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" (Merskey, 1986).

From this definition we see that pain is a perception in the same way that vision and hearing are. By this I mean that its significance is determined by the cerebral cortex in the light of other activity there. It involves sensitivity to chemical changes in the tissues and then interpretation that such changes are, or may be harmful. This perception is real, whether or not harm has occurred or is occurring. Cognition is involved in the formulation of this perception. There are emotional consequences, and behavioral responses to the cognitive and emotional aspects of pain.

Pain may be classified in many ways.

As a clinician dealing with soft tissue trauma, I have found it helpful to think of pain as being peripheral or central in origin. Peripheral pain originates in muscles, tendons, etc., or in the peripheral nerves themselves. Pain originating in the peripheral nerves, i.e. via trauma to the nerves, is neurogenic pain. Central pain arises from central nervous system pathology ... a "primary" CNS dysfuntion. Some of this may arise due to maladaptive thought processes, true "psychogenic" pain. But MOST of it is due to structural changes in the CNS, e.g., spinal cord injury, multiple sclerosis, stroke and epilepsy (Boivie, 1996).

Another classification, that distinguishes between normally functioning nerves and nerves whose function has been altered by pathology is as follows:

• Nociceptive pain is pain in which normal nerves transmit information to the central nervous system about trauma to tissues (nocere = to injure, Latin).
• Neuropathic pain is pain in which there are structural and/or functional nervous system adaptations secondary to injury, that take place either centrally or peripherally (Jensen, 1996). Much of what has previously been considered psychogenic pain is now better understood as neuropathic pain of central origin. The IASP defines central pain as "pain initiated or caused by a primary lesion or dysfunction in the central nervous system" (Merskey, and Bogduk, 1994). "Neuropathic" should not be confused with "neurogenic", a term used to describe pain resulting from injury to a peripheral nerve but without necessarily implying any "neuropathy".

The persistent pain often experienced in chronic work-related musculoskeletal injuries, as well as in those with long continued pain for other reasons, may persist because of a Central Nervous System dysfunction. But this is a CNS dysfunction secondary to long continued peripheral pain.

With this introduction we can now begin to follow the pathways by which information is transmitted centrally and is ultimately perceived as pain. It travels to the spinal cord or brainstem as a train of electrical impulses in C fibres or A delta fibres of spinal or certain cranial nerves. After crossing the synaptic junction through an extremely complex series of chemical interactions the, signal passes once more electrically to higher CNS levels in Nociceptive Specific, or less pain specific Wide Dynamic Range neurons.

We shall examine in turn peripheral nerve sensitivity, dorsal horn transmission, dorsal horn pathophysiology, supraspinal modulation of the nociceptive signal, ascending pathways, and cortical reception areas involved in pain perception. While doing so we should keep in mind an expression of Dr Ken Casey, "Nociception is born in the dorsal horn, but we don't call it pain till it reaches the brain" (IASP Conference, Vancouver, August 1996).

Peripheral Nerve Sensitivity

Tissue damage results in a drop in pH and release of chemicals, e.g. histamines and bradykinin, to which small non-myelinated C fibres are sensitive. Fitzgerald and Woolf (1984) have hypothesized that C fibres are primarily chemical sensors, although they do respond also to high level mechanical and thermal stimulation. The C fibres respond by generating an electrical impulse which travels along the nerve to the dorsal horn of the spinal cord. Activity of the C fibres may be up-regulated peripherally by serotonin (i.e., 5-hydroxy tryptamine), prostaglandins, thromboxane, and leucotrienes in the damaged tissues. This is referred to as peripheral sensitization in contrast to central sensitization which occurs at the dorsal horn. Both occur in chronic pain. Substance P may also be released peripherally with resultant increase in peripheral vasodilation and further sensitization of the C fibre's peripheral ending. Even chemical products of tissue breakdown may sometimes enter the neuron and be transported centrally to exert an effect at the dorsal horn synapse.

Dorsal Horn Transmission

At the dorsal horn, in addition to releasing substance P, C fibres release other excitatory neurotransmitters: glutamate, aspartate, calcitonin gene related peptide (CGRP), and a gas, nitric oxide (see Jensen, 1996, fig.1, p.82). There is some confusion over nitric oxide. Its exact role remains to be fully defined, and it is known to be produced on the other side of the synapse in addition to many other places. Neurotransmission is extremely complex involving:

• all six layers of the dorsal horn (primarily layers one, two, and five)
• influx of sodium and calcium ions from the interstitial spaces and outflow of potassium ions from within the nerve cell.
• temporal summation. If a stimulus arrives at the synapse in the dorsal horn more frequently than once every 3 seconds, the post-synaptic electrical discharge becomes more prolonged, with consequent increase in the severity of the pain.This temporal summation is termed "windup". To explore further the relationship between windup and central sensitization see Price (1999), p.90-96.
• competition for opporunities to stimulate ascending pathways. It is at this level that encephalin-producing descending fibres from the brain stem interact with both pre-synaptic and post-synaptic cells to inhibit transmission. Also at this level, at what has been called the "pain gate" by Melzack and Wall, incoming signals in the A beta fibres of a peripheral nerve can alter sensitivity of the post-synaptic cells to painful stimuli arriving in C and A delta fibres. For further information see Jensen (1996).

Dorsal Horn Pathophysiology

Neuropathic changes can occur, especially when pain persists. The nature of these, the circumstances under which they occur, as well as how to prevent and even reverse them, is the focus of much current research. The following is by no means a complete description, and is given to stimulate further reading.

• Central sensitization is characteristic of chronic pain. With long continued stimulation, there are physiological changes.But many are structural in nature. For example, changes in expression of genes (e.g.,c-fos and c-jun) occurs within the secondary (e.g., spinothalamic or spinoreticular) neurons that arise in the dorsal horn. These genetic changes affect the volume and type of enzymes and neuropeptides produced. Thereby they induce long term changes in these post-synaptic cells. One of these changes is that nerve growth factor begins to be produced in sufficient quantities as to promote alteration in patterns of nerve connections in the dorsal horn of the spinal cord at or about the level of incoming pain fibres. This structural reorganization in the spinal cord's dorsal horn is one factor that can explain "abnormal" spread of pain that is still referred to as "psychogenic" by those who, nearly four centuries later, continue to view pain as Descarte did. Incoming fibres from a particular area are able to gain access to neurons ascending to conciousness that normally just carry information from areas some distance away, involving different levels of the spinal cord (Jensen, 1996). For example, after crushing the sciatic nerve in rats there is initially hyperalgesia (an exaggerated response to painful stimuli) in the skin supplied by the sciatic nerve. After a few days, there is hyperalgesia well beyond this area, even in the area supplied by the femoral nerve. Hoheisal et al (1994) and Mense et al (1997), members of the same team, have shown similar effects when the sciatic nerve is stimulated after the gastrocnemius-soleus muscle in rats has become inflammed.
• Dorsal ganglion reflexes may be generated. Under certain conditions there can be reflex activation of the incoming sensory fibre. This not only reinforces the incoming stimulus; it also sends a retrograde electrical impulse which discharges substance P peripherally into the tissues, with consequent increase in inflammation.
• Volume transmission is the extrasynaptic spread of neuroactive molecules well beyond their target sites. These substances may lead to long term potentiation of primary afferent neurotransmission and lasting changes in both neuronal excitability and gene expression. This mechanism may also be involved in the spread of pain perception beyond the area of injury.
• Several supraspinal pain modulating loops exist. These can increase or decrease the amount of pain.
• Other descending anatomical pathways exist that are primarily inhibitory, but some may facilitate pain perception. These and the supraspinal modulating loops will now be briefly described. Much less is known about them than about lower level CNS changes, but research continues daily to bring us more information.

Supraspinal Modulating Loops

Inhibition of pain is essential at times when safety is more important, as when fleeing from danger. Yet pain is intended to tell us when something needs to be done about a damaged area. The brain is supposed to help us sort out whether to pay attention to the painful area or ignore it. So it should not surprise us that there are mechanisms to draw our attention to a source of pain, and others to help us overlook it. Cognitive Behavioral Therapy, as a treatment of chronic pain, makes use of the following anatomical pathways, many of which are called antinociceptive because they carry stimuli that inhibit pain perception.

It has been known for some time that the reticular formation of the brain stem is involved in either facilitation or inhibition of perception of pain under the influence of cortico-reticular signals. It was assumed there was one spinoreticular/reticulospinal loop on each side of the body. It is now known there are at least five on each side, that these pass information in both directions, and may be inhibitory or facilitatory. They connect the spinal cord to the following areas of the brainstem:

1. the dorsolateral pontine tegmentum
2. the rostral ventral medulla
3. the dorsal medulla
4. the caudal medulla
5. the lateral hypothalamus

The effect of stimulating some of these centres can last from an hour to several days. There are pharmacological as well as anatomical distinctions between them.

Other Descending Pain Modulating Pathways

These arise in the:

• cerebral cortex and pass to the
  • nucleus gracilis and cuneatus
  • reticular formation
  • thalamus
• periaqueductal grey matter and pass to the
  • dorsal horn directly
  • raphe nuclei of medulla, and then to dorsal horn
• locus ceruleus and pass to the
  • dorsal horn of spinal cord

Spinocerebral Ascending Pathways

The first two have been well recognized for many years. The others have more recently been described, or earlier suggested and only recently accepted by all. There may yet be others, whose complexity makes them harder to define.

1. The spinothalamic pathway crosses the midline and ascends on the opposite side of the spinal cord to the ventral posterolateral nucleus of the thalamus. This nucleus is subdivided for specific areas of the body, and each area projects to its own section of the primary sensory cortex -- a thin band of cortex in the parietal lobe just posterior to the central sulcus.This discriminative pathway transmits to conciousness precise information about the location of pain.
2. The spinoreticular pathway ascends on both sides of the spinal cord to the intralaminar nuclei of both the right and left thalamus. From there the next neuron in the chain takes the information to many areas of the brain, e.g., the anterior part of the cingulate gyrus ( emotion ), the amygdala ( memory and emotion ), and hypothalamus ( emotion and the vascular response to emotion ). Unofficially I like to call it the "suffering" pathway.
3. The dorsal column pathway has long been suspected of transmitting visceral nociception to the thalamus (as well as somatic touch and position sense). Now this is known to be so (Hirshberg, et al, 1996 ).
4. The spinomesencephalic tract has been described travelling with the spinotectal tract to the periacqueductal grey matter and superior colliculus of the midbrain. This may be the same as, or related to, the pathway travelling to the parabrachial nucleus in the brainstem -- which in turn projects to the amygdala, hypothalamus, and other limbic system stuctures in the forebrain.
5. The spinohypothalamic pathway is a very recently described route which does not synapse in the reticular formation. It carries information of emotional significance from the skin, lips, sex organs, gastrointestinal tract, intracranial blood vessel tongue and cornea directly to the hypothalamus.

Clearly there is one pathway that is concerned with a discriminative analysis of pain, but many others that concern our reactions to it, and feelings about it. One, we could say, engages "the mind", while the others involve the whole person.

Is there a "Cortical Pain Centre"?

Unfortunately there is no discrete centre where pain is recognised. Pain is so important to survival that almost the whole brain is involved. Pain involves cognition, emotion, and behaviour. Therefore it is not surprising that PET scan data obtained during painful stimulation indicates activity in the following cortical areas. Brodmann's tissue classification follows in brackets.

1. sensory and motor cortex areas..................................(1-4)
2. premotor cortex ( for planning of movement ).................(6)
3. other parts of the parietal cortex..................................(7 and 37-40)
4. other parts of the frontal cortex....................................(8-10 and 43-47)
5. cingulate cortex.......................................................(24 and 32)
6. insula........................................................................(14)
7. occipital cortex...........................................................(19)

Pain also projects to the following subcortical structures:

thalamus, putamen, caudate nucleus, hypothalamus, amygdala, periaqueductal grey matter, hippocampus, red nucleus, pulvinar, and vermis of the cerebellum (Wall,1996).

All of this supports Dennis Turk's claim that "the reign of pain is mainly in the brain". But there is no one centre "in control". Rather we see that pain can be all-pervasive, affecting our thoughts and memories, attitutudes and emotions, movements and behaviour -- and in turn be affected by each and all of them.

More on Central Sensitization

"Unlike other sensory stimuli, relatively brief trains of activity in peripheral nociceptors have the ability to trigger long term changes in CNS circuitry and cause prolonged states of hypersensitivity. This 'central sensitization' contributes to an amplification of the noxious input and a spread of pain outside the original damaged region (secondary hyperalgesia) and the onset of pain from normally innocuous stimuli (allodynia). The central sensitization arises from increases in membrane excitability, strengthened excitatory synaptic outputs and reduction of inhibitory interneuronal activity, which in turn are regulated by shifts in gene expression, the production and trafficking of key receptors, channels, and downstream neuronal signalling pathways."

Dr. Eldon Tunks, Director of the McMaster Chronic Pain Clinic, after reading my article offered this information:

"There are treatments that may actually aggravate central sensitization pains--oxycodone working on kappa receptors, prolonged high dose opiod metabolites...excessive triptans or ergotamine for migraines, and untreated pain itself. It is also becoming clear there are some kinds of treatment that may have more specific advantages in treating central sensitization: gabapentin, pregabalin, tramadol, amitriptyline, buprenorphine, (and) ketamine, for example."

References

Boivie J, Central pain syndromes. In Campell JN (ed) Pain 1996 - An Updated Review , IASP Press, Seattle, p.23-29.

Dubner R, Basbaum A, Spinal dorsal horn plasticity following tissue or nerve injury. Chapter 11 in Walls PD and Melzack R (eds) Textbook of Pain, 3rd ed., 1994, Churchill Livingstone, Edinburgh, p.225-241.

Fitzgerald M, Woolf CJ, Axon transport and sensory C fibre function. In Chahl LA, Szolcsanyi J, Lembeck F (eds) Antidromic Vasodilation and Neurogenic Inflammation, 1984, Akademiai Kiado, Budapest, p.119-140.

Hirshberg RM, Al-Chaer ED, Lawand NB, Westlund KN, Willis WD, Is there a pathway in the posterior funiculus that signals visceral pain? Pain 1996; 67: 291-305.

Hoheisel V, Koch K, Mense S, Functional reoorganization in rat dorsal horn during experimental myositis. Pain 1994; 59: 111-118.

Jensen TS, Mechanisms of neuropathic pain. In Campbell JN (ed) Pain 1996 - An Updated Review, IASP Press, Seattle, p.77-86.

Mense S, Hoheisel V, Kaske A, Reinert A, Muscle pain: Basic mechanisms and clinical correllates. Chapter 32 in Jensen TS, Turner JA, Wiesenfeld-Hallin Z (eds) Proceedings of the 8th World Congress in Pain Research and Management, 1997; 8: 479-496.

Merskey HM, Pain terms. Pain 1986; suppl. 3: S 215- S 221.

Merskey HM, Bogduk N, Classification of Chronic Pain , 2nd ed., 1994, IASP Press, Seattle, p.211.

Price DD, Psychological Mechanisms of Pain and Analgesia, 1999, IASP Press, Seattle.

Wall PD, The mechanisms by which tissue damage and pain are related. In Campbell JN (ed) Pain 1996 - An Updated Review, IASP Press, Seattle, p.123-126.

Fitzgerald M, The development of pain mechanisims, pain effects and pain expetiences in infants and children. Chapter 38 in Mogil J (ed) Pain 2010 - An Updated Review, Refresher Course Syllabus, IASP Press. Seattle, p.383-289.

Ranney D: A proposed neuroanatomical basis of Waddell's nonorganic signs. American Journal of Physical Medicine and Rehabilitation, 2010;89: 1036-1042.

A Recent Development in Treatment.

About the Author

Where he Still Works even though Retired
writing up recent research on work-related muscle pain.

Created by: ranney@hsfx.ca 1997/04/14

Revised by: ranney@hsfx.ca 2011/11/19