Basic Science of Chronic Pain

Pain initially develops in nociceptors, which are specialized nerve endings that are activated by temperature, incision, abrasion, and inflammatory chemicals produced by an injury.  Substance P is a skin neurotransmitter for pain. The impulses travel to the spinal cord with most impulses arriving through the dorsal root, although recent evidence demonstrates up to 40% of pain fibers enter through the ventral root (which was long thought to contain only  motor nerve fibers).  Once the fibers enter the spinal cord, they travel up several ascending pathways on the opposite side of the spinal cord.  The pain sensation is then routed to two different systems: paleospinothalamic which produces a diffuse ache and is difficult to localize and the neospinothalamic system which allows for perception of different shades of pain and permits localization. The signals are modified by the dorsal columns which act as “gates” and are acted on by descending inhibitory pathways from the brain that include the GABA system, NMDA systems, AMPA systems, etc.  Pain signals continue to ascend into the medulla and pons, the lowest parts of the brain where they are further modified and travel through several “nuclei” that are relatively well defined areas that have connections with other centers in the medulla.  Next, the signals travel to the thalamus which serves as a switching station.  The lateral signals are sent to the primary sensory cortex of the brain, where location perception is found.  The medial thalamic signals pass to several other areas of the brain including the cingulate gyrus which lies over the ventricles of the brain, the insula, and into the secondary sensory cortex.  These medial signals are part of the primitive system which allow for pain perception, but not localization or discrimination into shades of types of pain. 

Chronic pain is somewhat different than acute pain since often the nociceptors have healed, there is no inflammatory substance peripherally, yet the pain is still perceived to be localized in a specific location.  Wide dynamic range neurons and low threshhold neurons in the spinal cord become active in chronic pain.  These transmit signals to the brain that are perceived as pain, when the problem is simply overactivity of these spinal neurons.  In chronic pain, G proteins become active at the cellular level which also cause greater signal transmission.  The descending inhibitory systems are compromised in chronic pain resulting in greater signal perception.

The discussion of pain transmission will continue below tracking the impulses from the skin to the brain.

Skin Nociceptors

Most nociceptors are dormant and respond only to strong stimulation. Once repetitive stimulation occurs, leukotrienes, bradykinin, potassium, and other inflammatory chemicals are released by damaged tissues which in turn sensitize the nociceptors to the point that they respond to non-painful stimuli including light touch. Pain receptors are solely free nerve endings of two types:  the fast acting type which is composed of lightly myelinated (myelin is a sheath around most nerves in the body that protect the nerve and speed the nerve impulses transmitted)  and the slow type which are unmyelinated nerve endings.  The fast type pain sensors are high threshhold (they require an intense stimulus to activate), are located in the superficial skin, and transfer signals that are perceived as acute sharp stinging pain and transmit the signals at a rate of  5 to 30 meters per second along A delta neurons.  The slower type fibers are deeper in the skin, transmit pain as a slower onset burning diffuse unbearable pain and transmit signals at a rate of 1-2 meters per second on unmyelinated Cneurons.  Both types have their cell body in the dorsal root ganglia, and synapse (connect with second order neurons) in the superficial layers of the spinal cord in Rexed lamina I and II.  After synapsing, most second order neurons travel across the cord and ascend to the medulla, pons, and thalamus in spinothalamic tracts.

Pain sensors in the skin are not the same as those for touch, vibration, etc.  The latter are complex structure sensors while those for pain are simply nerve endings.  Some of the other sensors are shown below:

 Meissners and Pacinian corpuscles detect rapid moving touch, especially in hairless areas.  Hair follicle movement serve the same purpose in hairy skin.  Merkel discs detect static touch.  The Iggo dome receptors are extremely superficial and contain up to 50 Merkel discs each which serve as an amplifier to detect even very very light touch.  Pacinian corpusles also detect vibration sense.

There are also thermoreceptors located very superficially in the skin to detect cold and heat and respond vigorously to temperature changes.  In the tendons and ligaments are proprioception sensors to permit the body to know location of extremities at any point in time.  The remainder of this discussion will focus on pain transmission.

Once the neurons carry the pain impulses into the spine via the dorsal horn, the pain sensation is transferred to another neuron which carries the signal to the brain in the lateral spinothalamic tracts.  The neospinothalamic system transmits pain that is sharper, is discriminative (permits the person to localize the pain to a certain area of the body), and is the phylogenetically more modern system.  The paleospinothalamic system is the primitive transmission system for diffuse pain, is motivational-affective (does not permit exact localization, but tells the body it is hurt and needs to do something immediately to avoid continued hurting).  Note that the nerves coming into each system enter the dorsal (posterior) part of the spinal cord, synapse (connect with another neuron) in the dorsal horn which then crosses to the opposite side of the spinal cord, and then begins to rise in the spinothalamic tracts.  The neospinothalamic tract runs directly to the thalamus without any modulation or other input.  Contrarily, the paleospinothalamic tract runs to the medulla first, receives input from other areas of the brain, then to the pons nuclei, then to the thalamus.   The paleospinothalamic tract therefore modifies the signals prior to the thalamus.  This is actually a quite simplistic view because of complicated spinal cord structures within the tracts.  The anterior reticular formation, which is most prominent in the medulla, is a multineuron system that modifies impulses from the paleospinothalamic tracts.  Below are shown some of the more common tracts in the spinal cords and their functions:

 The lateral spinothalamic tract which transmits most pain and temperature is number 5, while the anterior spinothalamic tract which transmits crude touch and pressure is number 15.  Numbers 1 and 2 are the dorsal columns which transmit fine touch, proprioception, and vibratory sensation.  Tract 8, the spinotectalis, is a reflex tract to vision and head turning which causes a reflex glance when pain is perceived.

The medulla obligata is a structure that primary functions to modulate the affective type of pain through a series of nuclei.  There are other important nuclei in the medulla such as the chemoreceptor trigger zone which lead to nausea and may be activated during severe pain.  There are many descending inhibitory systems in the medulla to modulate the pain, especially near the raphe.  These systems inhibit pain.  The spinothalamic tracts, except for the paleospinothalamic tract, bypasses the medulla nuclei traveling in the lateral aspect of the medulla on the way to the thalamus.  The spinothalamic tracts continue on through the Pons, where the paleospinothalamic tract is again modified.  The locus coereleus is an important nucleus in the pons that further modifies pain signals.  In conditions of sudden fear or shock, the locus coereleus produces glutamate and 5-HT, a precursor to serotonin.  These modulate pain by decreasing transmission beyond the locus.  Contrarily, a conditioned, expected response does not increase these levels.  This implies that sudden fear reduces pain while chronic anxiety over expected pain can increase pain, which is certainly seen clinically. 6th Internet World Congress for Biomedical Sciences  Presentation #27

The midbrain has a large number of structures which modify pain from the paleospinothalamic tracts including the peri-aqueductal grey matter (very high concentration of narcotic receptors), deep layers of the superior colliculus, the red nucleus, the pre-tectal nuclei (anterior and posterior), the nucleus of Darkschewitsch, the interstitial nucleus of Cajal, etc.  These areas have extensive connections with the reticular matter of the brainstem.  This reticular matter is involved in the modulation of incoming pain signals.  The primitive sensory somatic nervous system (affective/motivational) comes from tracts deep in the spine and project to the reticular system located just under the midbrain. 

The pain impulses continue to rise into the thalamus .  The thalamus is a two lobed part of the brain that exists on top of the brainstem.  One lobe is shown on the left. It acts as a relay station for several senses including auditory, vision, and pain.  The thalmus contains several nuclei, or relay stations.  The ventral posterio-lateral nucleus (VPL) is the main switching station for pain, receiving input from the spinothalamic tracts of the spinal cord and relaying the information to the cortex.  The VPL is thought to mainly be concerned with discriminative functions: location of pain, etc.  The medial nuclei are more involved in affective/motivational components of pain.  Of significance is the convergence of several different tracts on the VPL of the thalmus, including vibration and positional sense, light touch, pain, and temperature.  Some patients with chronic pain have aberrations in all these senses which may indicate a thalamic process of maintaining pain.  In addition to both spinothalamic tracts converging on the thalamus, there are extensive connections between the limbic system and the thalamus. The limbic system surrounds the thalamus, and is responsible for motivational behaviors such as eating, flight, anger, and sex.  The amygdala is responsible for aggression and aggressive behavior while the cingulate cortex is responsible for the emotional response to pain.  The septum regulates anger and pleasure.  Short term memory is imprinted in the hippocampus.  There are many connections between the limbic system and the thalamus.  Obviously, the limbic system is affected by pain and affects pain perception through connections with the thalamus.  The thalmus has many projections to the cerebral cortex, where perception is achieved.  In the brain, pain is perceived as two different sensations in specific anatomic areas.  The phylogenetically primitive affective-motivational aspect of pain is diffuse, carried by primitive paleospinothalamic tract  This affective aspect is perceived as a “soreness” or a “hurt” and provokes action to stop the pain.  Contrary to this type of pain is the sensory/discriminative type of pain which allows a person to perceive pain as originating from a specific location.  The affective type of pain is perceived in the cingulate gyrus and insula along with the secondary sensory cortical strip.  The sensory/discriminative type of pain is perceived in the primary cortical sensory strip

Recently, there have been developed new types of imaging which include PET (positron emission tomography) and fMRI (functional magnetic resonance imaging) have given pain projection information in the brain.

The image on the right is a fMRI image of pain with increasing intensity over time.  The areas in red (primary sensory cortex and anterior cingulate gyrus) show increasing signals (graph B) that correlate directly to pain intensity (graph A).  However most interesting are the areas in green in the frontal cortex which show decreases in oxygen use (graph C) over time with increasing pain.

Descending Pathways Modulating Pain

As has been inferred above, there are not only modulations of pain as it ascends through the brainstem and brain, but also through descending systems which travel as far as the entry point of the nerves into the spinal cord.  From the periaquaductal grey (PAG), serotonin neurotransmitter tracts project into the lateral spinal thalamic tract (B) or sequentially into the dorsal horns (C-D).  These modulate and decrease the input from the dorsal nerve root (A).  Stress, anger, lack of sleep can reduce the serotonin stores, thereby allowing more pain signals to reach the brain.

Chemical and Genetic Components of Pain

Excitatory neurotransmitters in the spinal cord and brain include glutamate, neurokinins, calcium gene reactive peptide, somatostatin, vasoactive intestinal polypeptide, bombesin.

The glutamate group includes NMDA, AMPA, and metabotropic receptors.  The NMDA is the most studied of the group.  Inhibition of NMDA receptors cause a reduction in pain transmission.  NMDA receptors are usually inactive, being linked to an ion of magnesium that plugs the ion channel.  During times of prolonged pain, the magnesium ion is displaced, allowing certain neurons to become hyperactive, and can even spontaneously fire.  This phenomenon is called “wind-up”.  Also produced by glutamate system activation are spinal prostanoids, c-fos, and nitric oxide.  Probably equally important, but inadequately studied are the AMPA and metabotrophic receptors.  The tachykinin system consists of calcium channel receptors responsive to substance P and neurokinin A and B.

Inhibitory neurotransmitters include GABA and GABA linked systems, and glycine.  GABA is over 40% of all inhibitory transmitters in the central nervous system and is especially prominent in the dorsal horns of the spinal cord, acting as a “gate” to allow passage of selected impulses.  There are at least two types of GABA receptors.

Descending tract modulation neurotransmitters include serotonin, norepinephrine, and endogenous opiates.

Genetic expression  There are three genes which have been discovered which are inducible with protracted C fiber or visceral pain impulses: c-fos, Jun, and Krox. C-fos produces a protein called Fos, which causes G proteins in the cell wall of neurons to become more permeable, transmitting more impulses. With prolonged pain stimulation, c-fos expression becomes intractable, except in spinal neurons, where it completely disappears 2-7 days after the onset of chronic pain production.  But c-fos is expressed in many nuclei of the midbrain, pons, thalamus, limbic system, and cortex.  C-fos seems to induce other gene transcriptions such as that of some of the opiate systems.


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