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Gate Theory of Pain Modulation

Contents

Overview

Pain is a constant nuisance to many individuals. It can be a representation of actual injury (such as blunt force trauma to a limb) or emotional injury (such as the pain of a broken heart). As such, pain can be defined as a subjective perception of noxious stimuli. The International Association for the Study of Pain coined a more appropriate definition to encompass the above mentioned concept:

  • Pain is an unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage.

Pain can be classified temporally (acute versus chronic) or based on the site of origin (visceral versus somatic). Acute pain, as the name suggests, occurs suddenly and usually follows very recent insult (iatrogenic trauma, myocardial infarction). Chronic pain has a more protracted course progressing over months to years. It may be further subdivided into nociceptive and neuropathic pain, based on the cause of the injury along the neuronal pathway. Nociceptive pain results from stimuli that can result in tissue damage. Possible causes of nociceptive pain include sickle cell crises, sports injuries, mechanical pain or postoperative pain. On the other hand, neuropathic pain is a result of dysfunction of the nervous system or a lesion within the same. This is the typical pain felt in cases of trigeminal neuralgia, diabetic neuropathy, and cancer. It is possible that both nociceptive and neuropathic type pains can occur simultaneous to give a mixed type pain.

Pain originating from internal organs – also called visceral pain – is often described as a dull, aching or throbbing pain that cannot be localized. The difficulty with localizing the source of visceral pain stems from a phenomenon known as referred pain. This is a situation in which pain originating from one part of the body is perceived elsewhere. For example, pain associated with pancreatitis is often felt in the epigastrium (around the region of the xiphoid process) and radiating to the back. Another (more familiar) example is the pain associated with myocardial infarction, which is said to radiate up the left side of the neck, towards the left shoulder and along the left arm. This differs significantly from somatic pain, which arises from cutaneous and subcutaneous tissue, as well as musculoskeletal structures. The exact location of this type of pain can be localized to an exact point.

This article aims to look at the anatomical structures associated with pain perception in addition to examining the Gate Theory of Pain modulation.

Pain Pathway

The process of converting noxious stimuli into action potentials involves several steps. Firstly, tissue damage can occur secondary to chemical, thermal or mechanical insults. These events are detected by nociceptors; which are Aδ (A-delta; myelinated with a conduction rate of 20 m/s) and C (unmyelinated with a conduction rate of 2 m/s) fibers. The Aδ fibers transmit pain stimuli at a faster rate than C fibers. As a result, Aδ fibers is involved in protective spinal reflex arcs that causes individuals to withdraw from a noxious stimulus; while C fibers facilitate the transduction of slow, burning type pain. In response to the stimuli, nociceptors transduce this information into nerve impulses by releasing a myriad of neurotransmitters such as prostaglandins, bradykinins, substance P and histamine, which all promote an inflammatory response and simultaneously propagate pain signals to the spinal cord.

The action potential associated with this event is propagated along the nociceptors and carried to the dorsal horn of the spinal cord. Within the dorsal horn of the spinal cord, the nociceptors diverge cranially and caudally for two to three spinal segments, forming the dorsolateral tract of Lissauer. At these levels, nociceptors (first order neurons) then synapse with the cell bodies of the fibers of the spinothalamic tracts (second order neurons) at varying layers of the dorsal column known as Rexed laminae:

  • Rexed lamina I (dorsomarginal nucleus) – responding to thermal or noxious stimuli to the skin.
  • Rexed lamina II (substantia gelatinosa) – believed to regulate sensory input.
  • Rexed laminae IV – VI (nucleus proprius) – also called the deep dorsal column nuclei, these cells respond to cutaneous stimuli as well as afferent information from visceral and deep somatic receptors.
  • Rexed laminae VII & VIII – are responsible for transmitting deep somatic stimuli from muscles and joints.

Spinal Cord - Ventral View

Spinal cord - ventral view

The fibers of the spinothalamic tract leave the dorsal column and decussate in the anterior white commissure of the cord. Fibers concerned with pain and thermal sensation coalesce in the lateral funiculus (with the ventral spinocerebellar tract forming its lateral border) to form the lateral spinothalamic tract. Those fibers concerned with light touch and pressure sensation congregate in the anterior funiculus to form the ventral spinothalamic tract. These tracts have a somatotopic arrangement from lateral to medial: sacral fibers, lower limb fibers, trunk fibers and upper limb fibers. This arrangement is maintained throughout the ascending circuit. The spinothalamic tract takes this information to several central points for integration and processing. It gives off the spinoreticular fibers, which in turn synapse with neurons of the nucleus raphe magnus in the medulla oblongata. At the level of the midbrain, it gives branches that synapse with cells of the periaqueductal grey matter, nucleus raphe dorsalis, and the reticular formation. The rest of the fibers of the tract terminate in the ventral posterolateral and intralaminar nuclei of the thalamus.

From the thalamus, third order neurons travel through the posterior limb of the internal capsule and terminate at corresponding somatotopic areas of the somatosensory cortex (Brodmann area 3, 1, 2). The cerebral cortices not only allow conscious perception of pain, but it also stimulates the hypothalamus, amygdala and periaqueductal grey matter, which in turn inhibits pain transmission via the release of endogenous opioids, norepinephrine and γ-aminobutyric acid (GABA).

Gate Theory

In 1965, Melzack & Wall theorized that there were systems in place that modified the passage of impulses that travel along afferent (including nociceptive) pathways. The basic concept of gate theory is that the activity of inhibitory interneurons suppress the ascending nociceptive signals and act like gates to decrease transmission. They postulated that small unmyelinated afferent fibers inhibit interneurons but excite cells of the spinothalamic tract; while larger afferent cells (such as those arising from touch corpuscles and hairs) excite the large neurons of lamina IV and interneurons of substantia gelatinosa. The previously mentioned interneurons are nerve fibers that complete the complex reflex arcs within the grey matter of the spinal cord. Rexed lamina II or the substantia gelatinosa is believed to house interneurons that regulate the transmission of pain by inhibiting transmission along both small and large diameter afferent fibers. When activated, they inhibit subsequent afferent fibers that form synapses with tract cells. As a result, bouts of low frequency afferent transmission along small fibers results in inhibition of the interneurons of substantia gelatinosa cells. As a result, afferent sensation from the large diameter fibers travel unopposed (albeit intermittently) to the spinothalamic tract cells of lamina IV. Hence the “gate” to lamina IV would be sporadically opened. This results in an initial large transmission along the large fibers that would gradually taper off as the “gate” closes (small afferent activity decreases).

On the contrary, if the impulses arising from the small afferent fibers were strong and persistent, the “gate” would be opened and a high volume of stimuli would be transmitted to lamina IV cells. This would therefore result in a greater degree of supraspinal perception of pain.

Clinical Significance

To some individuals, pain is a warning signal alerting them that something has gone wrong or is about to go wrong. On the other hand, those experiencing these sensations are likely to be perturbed and uncomfortable. However, pain may have more deleterious effects on various body systems that warrant immediate management.

The experience of pain is a stressful event that is often associated with fear and anxiety. Consequently, the sympathetic nervous system is activated during this time; which corresponds with the release of various catecholamines. These catecholamines will promote vasoconstriction resulting in increased systemic vascular resistance, and by extension increased blood pressure. This is often associated with an increased heart rate that can result in an overall increase in myocardial demand. If the myocardial demand for oxygen exceeds the supply, then it is possible that the particular patient may experience a myocardial ischemia.

Pain to the thoracoabdominal region, particularly following surgical procedures, is likely to result in patients deliberately taking shallow breaths. This hypoventilation (particularly in this state of high oxygen demand and elevated carbon dioxide production) can result in the patient becoming hypoxaemic (low oxygen concentration in the blood) and hypercapnic (high carbon dioxide concentration in the blood). A ventilation–perfusion mismatch may ensue, which not only precipitates the aforementioned cardiovascular complication, but also impairs wound healing.

As previously stated pain activates the sympathetic nervous system, which promotes the release of epinephrine, norepinephrine and other catecholamines. These neurotransmitters are designed to suppress gastric motility, resulting in a paralytic ileus (intestinal blockage without any physical evidence of an obstruction). As a result, gastric emptying will be delayed and gastric secretions can accumulate within the stomach. This scenario will put the patient at risk for developing stress ulcers (as the gastric acids act on the mucosa of the stomach), aspiration pneumonia, as well as nausea, vomiting and constipation. Furthermore, stimulation of central pain receptors also stimulates the vomiting centre, which may further precipitate nausea and vomiting.

By activating the sympathetic system, pain also causes the release of a myriad array of hormones that have implications on other systems. These include:

  • Renin is released from the juxtaglomerular cells of the kidney and indirectly stimulates the release of angiotensin II and aldosterone via the Renin-Angiotensin-Aldosterone System (RAAS). Aldosterone promotes sodium retention and by extension water reabsorption; while angiotensin II stimulates vasoconstriction. Therefore, by increasing intravascular volume and decreasing peripheral resistance, the RAAS pathway results in increased blood pressure that may affect the cardiovascular system.
  • Glucagon is another sympathetic hormone that promotes the conversion of stored glycogen into glucose, which can be used as an energy source. However, this increase in blood sugar level may be detrimental to patients who are already diabetic and have difficulty regulating their blood sugar levels.

There is a subjective component to pain perception that makes it difficult to assess how much pain a person could be in. Some clinicians refer to pain as the fifth vital sign. It may be indirectly quantified using several pain scales. Verbal and Numerical rating scales can be used to help adults and older children to relay the degree of pain. For younger children, a Visual Analogue or Faces (Wong-Baker) scale would be more appropriate. For the Numerical Scale, the patient is asked to rate their pain on a scale of 0 – 10, with 0 being no pain and 10 being the worst possible pain, ever.

In addition to the physical aspect, there is a psychological element to pain. The constant sensations can cause patients a significant degree of anxiety and distress. As a result, it is extremely important to adequately manage a patient’s pain irrespective of how “simple” a situation may look.

There are pharmacological and nonpharmacological methods of managing pain; however, this article will only briefly explore pain management as both topics are deserving of their own articles.

Pharmacological pain management can be executed at all four levels of the pain pathway (transduction, transmission, perception and modulation). Non-steroidal anti-inflammatory drugs are a class of pharmaceuticals that work by inhibiting the production of prostaglandins via the downregulation of the cyclooxygenase enzyme (COX inhibitors). These include ibuprofen, acetaminophen and celecoxib. These drugs act at pain receptors (transduction) to minimize the transmission of pain impulses.

Local anaesthetics act at the level of sodium channels on the nerve cell membrane to limit the propagation of action potentials along the same. As a result, pain and other impulses cannot be transmitted along these neurons. These drugs include lidocaine, bupivacaine and the most notorious, cocaine (to name a few). Other centrally acting drugs, such as the opioids (morphine, fentanyl, and remifentanil) act on opioid receptors to modify the perception of painful impulses.

The World Health Organization (WHO) has suggested a stepwise approach to delivering analgesia known as the WHO Analgesic Ladder. The proposition is based on the severity of pain being perceived by the patient and the efficacy of the drug in their particular situation. Step one suggests the use of less powerful non-opioid drugs such as aspirin or NSAIDs. If the pain persists or worsens, then weaker opioids such as codeine may be used in conjunction with a non-opioid. Finally, if the previous modalities failed, then strong opioids such as morphine alone or in combination with a non-opioid may be used in an attempt to achieve analgesic control.

Combination therapy is helpful in pain management as it allows the physician to approach pain management from multiple pathways while reducing the amount of each drug being used. The latter will also reduce the amount of adverse drug reaction the patient experiences as a result of each drug being used.

Transcutaneous Electrical Nerve Stimulation (TENS) therapy is a nonpharmacological form of pain management that is further subclassified as electroanalgesia. TENS directly exploits the concept of the gate theory. The TENS unit is a battery operated electrical-signal generator with several electrodes. The generators can be programmed to deliver impulses at specific rates (pulse rate), durations (pulse width) and currents (amplitude). The electrodes are attached to the skin over the painful area and the resulting electrical impulses will stimulate interneurons which prevents the propagation of nociception. Additionally, research supports the notion that TENS also increases the concentration of endogenous endorphins and enkephalins that provides analgesia via opioid receptors.

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References:

Author, Review and Layout:

  • Lorenzo Crumbie
  • Uruj Zehra
  • Catarina Chaves

Illustrators:

  • Spinal cord - ventral view - Begoña Rodriguez
© Unless stated otherwise, all content, including illustrations are exclusive property of Kenhub GmbH, and are protected by German and international copyright laws. All rights reserved.

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