Introduction
Pain, a somatic sub-modality, is necessary for functional human existence in the environment. Pain exists as a protective mechanism, making the individual aware of harmful stimuli in the environment. Besides acting as a protective mechanism, connections of pain receptors to cingulate areas of the cortex indicate the influence of pain in the control of movement (Dum 2009).
Clinically, there are many manifestations of pain transduction disorders. Some of these disorders include pain hyposensitivies and hypersensitivies, as well as a complete lack of pain perception (analgesia). A commonly seen pain disorder, hyperalgesia, is defined as an “enhanced sensitivity to normally noxious stimuli”, often “extending well beyond the site of injury and into undamaged skin” (Mizimura 1997). Hyperalgesia has peripheral and central origins: one of the peripheral mechanisms underlying hyperalgesia will be explored.
Hyperalgesia.png
Amplification of Pain Stimulus http://ir.nul.nagoya-u.ac.jp/jspui/bitstream/2237/16753/1/v60n34p69_87.pdf

Functional Anatomical Review and Physiological Mechanisms
Pain perception is similar to perception of other stimuli: an afferent signal is carried up the spinal cord, through the thalamus, eventually terminating in the cortex. Painful stimuli are sensed by pain receptors, nociceptors, free nerve endings dispersed throughout the body in the skin, joints, and viscera. Nociceptors must be stimulated by an adequate stimulus; skin nociceptors respond to mechanical, thermal, and chemical stimuli (Kandel 2000).

Like other nerve cells, nocicepters have a resting membrane potential between –80 mV and – 40mV. This resting membrane potential is due to a dynamic relationship between equilibrium potentials of Na+ (sodium), K+ (potassium) and other ions. The membrane of any given neuron has many different channels, regulating the concentration of these ions on either side of the cell membrane (Krants). Some of these channels include sodium/potassium pumps, voltage gated sodium and potassium channels, “leaky” sodium and potassium channels and acid sensitive ion channels (Mamet 2002). There is a constant efflux and influx of ions across the cell membrane, so that a resting membrane potential is established.

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Establishing the Resting Membrane Potential http://classconnection.s3.amazonaws.com/938/flashcards/1810938/png/screen_shot_2012-10-21_at_101505_pm1350872064464.png




In contrast to other proprioceptive stimuli, pain stimuli travel primarily through Ad and C fibers. Ad fibers, or group III fibers, are approximately 1-5 um in diameter, lightly myelinated fibers, with conduction velocities of about 5-30 m/s. C fibers, or group IV fibers, are approximately 0.2-1.5 um diameter, unmyelinated fibers with conduction velocities of about 0.5-2 m/s. The relatively slower velocities of these “pain” fibers results from their physical features: the small amount or lack of myelination, as well as the small diameter of these fibers predisposes these fibers to having a slower conduction velocity than the larger, more highly myelinated fibers of group I and II (Neuroscience online).

A-C fibers.png
Ad and C fiber pathways, http://neuroscience.uth.tmc.edu/s2/chapter06.html


For perception, painful stimuli ascend the spinal cord and eventually terminate in the cortex through the spinothalamic (also known as the anterolateral) tract. The spinothalamic tract lies in the anterolateral white matter of the spinal cord. First, Ad and C fibers enter the spinal cord through the dorsal horn. In general, fiber termination in the dorsal horn is organized according to the afferent fiber type: Ad fibers synapase in Rexed Laminae I and IV, and C fibers synapse in Rexed Lamina II. In the dorsal horn, primary nociceptive afferents synapse interlaminally with their corresponding secondary cell body. This cell body decussates at the level of entry and ascends the contralateral side of the spinal cord in the anterolateral pathway (Medical Neurosciences). This neuron terminates on a thalamic nucleus in the ventral posterior-lateral thalamus, which then terminates in the somatosensory cortex for perception (Davidson 2008).


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The Anterolateral System. http://www.neuroanatomy.wisc.edu/virtualbrain/BrainStem/02ALS.html

Peripheral Mechanisms of Hyperalgesia

Hyperalgesic patients experience a high sensitization to normal painful stimuli. There are many central and peripheral mechanisms by which this sensitization occurs. One mechanism by which peripheral sensitization occurs is through a lowering of the resting membrane potential of nocicepters. This mechanism involves an inflammatory mediated ion channel change.

In response to physical trauma, the body releases many inflammatory and pain mediators (Bradykinin, histamine, neurotrophins, cytokines). These substances are released to recruit macrophages and other immune cells to the site of trauma, so that the body’s immune defenses can regulate any further physical damage. Often, the high concentration of these chemical mediators in the extracellular fluid generates acute hyperalgesia by altering the membrane permeability of intracellular and extracellular ions. This change in membrane permeability brings the cell closer to threshold: the cell membrane is hypersensitized (Sandkühler 2009).

In the chronic phase, inflammation also stimulates the production of more acid-sensing ion channels on the cell membrane. With more acid-sensing ion channels on the cell membrane, the cell body will be hypersensitive to any increase in acidity (Mamet 2002). In addition, the inflammatory response recruits silent nociceptors, nociceptors that are usually unresponsive to noxious input. These silent receptors lie deeper in the skin and tissues; when activated, they create a perception of pain that is greater in magnitude and intensity than the original pain stimulus (Neuroscience online).



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A Schematic of a Hyperalgesic Mechanism http://physrev.physiology.org/content/89/2/707.full


Conclusion

There are many connections and convergences in the pathways to pain perception: the resting membrane potential of the primary nociceptor is subject to it’s fluctuating environment, which then effects the ascending pathways from the receptor up to the somatosensory cortex. Because of the many levels of integration in the pathways of pain perception, there are many other mechanisms by which hyperalgesia can manifest itself, both peripheral and central. Regardless of the mechanism, hyperalgesia will always manifest itself as “increased numbers of action potentials and spontaneous discharges in response to painful stimuli” (Marcus 2000).

A malignant perception of the environment, regardless of the stimulus, will alter how an individual responds to and interacts with their environment. The somatosensory and the motor cortex lie adjacent to each other and continuously interact with each other (Neuroscience online). The proximity of these cortices, as well as the termination of spinothalamic collateral axons in the cingulate motor areas of the cortex leads to the generation incorrect and often “timid” movements (Dum 2009). Besides effecting patients’ motor behavior, hyperalgesia can also induce anxiety and other psychological disorders.

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Overlap of pain and motor activity in the cerebral cortex. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2796243/


Treatment of hyperalgesia must be approached holistically. Besides drug therapy, electrical stimulation therapy, trigger point massages, and other pain attenuating approaches, physical and occupational therapy are often prescribed to patients who show symptoms of hyperalgesia. Some of these therapies include reconditioning and stretching exercises, as well as helping patients to regain control of body mechanics and pacing skills. Finally, hyperalgesia is often addressed in patients by providing stress management and relaxation therapy (Marcus 2000).

Glossary of Terms
- Ad fibers: lightly myelinated fibers, diameter: 1-5um, signal transduction velocity: 5-30 m/s
- C fibers: unmyelinated fibers, diameter: 0.2-1.5 um, signal transduction velocity: 0.5-2 m/s
- Cingulate motor region: brain region involved in motor, cognitive, and emotional tasks; located on the medial aspect of the cortex
- Decussation: crossing to the opposite side of the spinal cord
- Hyperalgesia: “enhanced sensitivity to normally noxious stimuli”, often “extending well beyond the site of injury and into undamaged skin”
- Myelin: electrical insulation of axons
- Nociceptors: free nerve endings in skin, joints, and viscera allowing for the perception of pain
- Somatosensory Cortex: final termination sight of all sensory projections in the cortex
- Thalamus: the gateway to cortex, all sensory signals to the cortex first go through the thalamus
- Threshold: the level of depolarization that leads to an action potential

Helpful links
http://www.youtube.com/watch?v=n2Jzt3zd8vQ&list=PL135D6D2DC7479E87&index=1
A video of pain pathways to the cortex.
http://www.ted.com/talks/elliot_krane_the_mystery_of_chronic_pain.html
Chronic pain video highlighting allodynia.

Quiz
True/False
1. T/F A normal stimulus that elicits a pain response is regarded as hyperalgesia.
2. T/F Hyperalgesia can be generated by peripheral and central mechanisms
3. T/F Nociceptors have no special nerve endings, they are free nerve endings
4. T/F Nociceptive signals terminate in the same lamina regardless of afferent fiber type
5. T/F The spinothalamic tract has collateral afferents that synapse in the cingulate motor area
Multiple Choice
1. Painful afferents travel by which of the following afferent fibers?
a. A- a fibers
b. C fibers
c. A- d
d. Both b and c
2. Where are nociceptors found?
a. Skin
b. Joints
c. Viscera
d. All of the above
3. C-fiber afferents terminate in which lamina?
a. Lamina I
b. Lamina II
c. Lamina III
d. Lamina IV
4. Which ion channels are increased on the cell membrane in response to inflammatory mediators?
a. “Leaky” sodium and potassium channels
b. Voltage-gated channels
c. Acid-sensitive channels
d. Sodium/potassium pumps
5. Where is the site of decussation in the ascending spinothalamic tract?
a. In the spinal cord level of entry
b. In the thalamus
c. There is no decussation
d. After leaving the thalamus
Short Answer:
1. Describe and discuss why nociception is crucial to proper functioning in the environment.
2. Where in the sensory processing can other potential sources of hyperalgesia occur?
3. Describe the asceding pathway of the spinothalamic tract, including site of entry, site of decussation, and termination sites.
Answers 1F, 2T, 3T, 4F, 5T 6d, 7d, 8b, 9c, 10a

References
1. Davidson S, Xijing Z, Khasabov SG, et. al. Termination Zones of Functionally Characterized Spinothalamic Tract Neurons Within the Primate Posterior Thalamus. J Neurophysiol 100: 2026-2037, 2008.
2. Dum RP, Levinthal DJ, Strick PL. 2009. The Spinothalamic System Targets Motor and Sensory Areas in the Cerebral Cortex of Monkeys. J Neurosci 29:14223-13245, 2009.
3. Kandel, ER, Schwartz, JH, & Jessell TM. Principles of Neural Science. New
York, NY: McGraw-Hill, 2000, 475-481.
4. Krants, JH. Review of Physical Factors Involved in the Action Potential. http://psych.hanover.edu/Krantz/neurotut.html
5. Mamet J, Baron A, Lazdunski M, Voilley N. ProInflammatory Mediators, Stimulators of Sensory Neuron Excitability via the Expression of Acid-Sensing Ion Channels. The Journal of Neuroscience 22(24):10662–10670, 2002.
6. Marcus DA. Treatment of Nonmalignant Chronic Pain. Am Fam Physician. 61(5):1331-1338, 2000.
7. Medical NeuroSciences. Brain Stem: Anterolateral System. http://www.neuroanatomy.wisc.edu/virtualbrain/BrainStem/02ALS.html/.
8. Mizumura, K. PERIPHERAL MECHANISM OF HYPERALGESIA SENSITIZATION OF NOCICEPTORS. Med. Sci. 60: 69 - 87, 1997.
9. Neuroscience Online: an electronic textbook for the neurosciences. Neurobiology and Anatomy at The University of Texas Medical School at Houston. http://neuroscience.uth.tmc.edu/
10. Sandkühler J. Models and Mechanisms of Hyperalgesia and Allodynia. Physiology Rev 89:707-758, 2008.