Sensory-Pain+Hypersensitivity

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. **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).
 * Introduction**

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.



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).



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).

**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).



**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.



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

<span style="font-family: Arial,Helvetica,sans-serif;">**Helpful links** <span style="font-family: Arial,Helvetica,sans-serif;">[] <span style="font-family: Arial,Helvetica,sans-serif;">A video of pain pathways to the cortex. <span style="font-family: Arial,Helvetica,sans-serif;">[] <span style="font-family: Arial,Helvetica,sans-serif;">Chronic pain video highlighting allodynia.

<span style="font-family: Arial,Helvetica,sans-serif;">**Quiz** <span style="font-family: Arial,Helvetica,sans-serif;">True/False <span style="font-family: Arial,Helvetica,sans-serif;">1. T/F A normal stimulus that elicits a pain response is regarded as hyperalgesia. <span style="font-family: Arial,Helvetica,sans-serif;">2. T/F Hyperalgesia can be generated by peripheral and central mechanisms <span style="font-family: Arial,Helvetica,sans-serif;">3. T/F Nociceptors have no special nerve endings, they are free nerve endings <span style="font-family: Arial,Helvetica,sans-serif;">4. T/F Nociceptive signals terminate in the same lamina regardless of afferent fiber type <span style="font-family: Arial,Helvetica,sans-serif;">5. T/F The spinothalamic tract has collateral afferents that synapse in the cingulate motor area <span style="font-family: Arial,Helvetica,sans-serif;">Multiple Choice <span style="font-family: Arial,Helvetica,sans-serif;">1. Painful afferents travel by which of the following afferent fibers? <span style="font-family: Arial,Helvetica,sans-serif;"> a. A- a fibers <span style="font-family: Arial,Helvetica,sans-serif;"> b. C fibers <span style="font-family: Arial,Helvetica,sans-serif;"> c. A- d <span style="font-family: Arial,Helvetica,sans-serif;"> d. Both b and c <span style="font-family: Arial,Helvetica,sans-serif;">2. Where are nociceptors found? <span style="font-family: Arial,Helvetica,sans-serif;"> a. Skin <span style="font-family: Arial,Helvetica,sans-serif;"> b. Joints <span style="font-family: Arial,Helvetica,sans-serif;"> c. Viscera <span style="font-family: Arial,Helvetica,sans-serif;"> d. All of the above <span style="font-family: Arial,Helvetica,sans-serif;">3. C-fiber afferents terminate in which lamina? <span style="font-family: Arial,Helvetica,sans-serif;"> a. Lamina I <span style="font-family: Arial,Helvetica,sans-serif;"> b. Lamina II <span style="font-family: Arial,Helvetica,sans-serif;"> c. Lamina III <span style="font-family: Arial,Helvetica,sans-serif;"> d. Lamina IV <span style="font-family: Arial,Helvetica,sans-serif;">4. Which ion channels are increased on the cell membrane in response to inflammatory mediators? <span style="font-family: Arial,Helvetica,sans-serif;"> a. “Leaky” sodium and potassium channels <span style="font-family: Arial,Helvetica,sans-serif;"> b. Voltage-gated channels <span style="font-family: Arial,Helvetica,sans-serif;"> c. Acid-sensitive channels <span style="font-family: Arial,Helvetica,sans-serif;"> d. Sodium/potassium pumps <span style="font-family: Arial,Helvetica,sans-serif;">5. Where is the site of decussation in the ascending spinothalamic tract? <span style="font-family: Arial,Helvetica,sans-serif;"> a. In the spinal cord level of entry <span style="font-family: Arial,Helvetica,sans-serif;"> b. In the thalamus <span style="font-family: Arial,Helvetica,sans-serif;"> c. There is no decussation <span style="font-family: Arial,Helvetica,sans-serif;"> d. After leaving the thalamus <span style="font-family: Arial,Helvetica,sans-serif;">Short Answer: <span style="font-family: Arial,Helvetica,sans-serif;">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. <span style="font-family: Arial,Helvetica,sans-serif;">**Answers** //<span style="font-family: Arial,Helvetica,sans-serif; font-size: 80%;">1F, 2T, 3T, 4F, 5T 6d, 7d, 8b, 9c, 10a //

<span style="font-family: Arial,Helvetica,sans-serif;">**References** York, NY: McGraw-Hill, 2000, 475-481.
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