Perception of Pain
PKGhatak, MD.
Pain sensation is an essential sensation utilized by all living creatures to avoid injuries and preserve life. The basic physiology of pain is known for a long time; the perception of pain is more than receiving pain sensation. The known areas of the cerebral cortex involved in pain appreciation and perception have expanded in recent years. This article is an attempt to bring the subject current.
Physiology of pain.
The skin is covered with special sensory receptors for touch, cold and heat, pressure and vibration. There are no special receptors for pain. The pain sensation is received by Free Nerve Endings. When any non-pain sensation exceeds a certain threshold, that sense turns into a Pain sensation.
Spinal nerves.
Three types of spinal nerve fibers carry sensations from the skin – delta fiber, C-fiber and AB-fiber. The delta fibers are thinly myelinated and carry pain and change of temperature sensations at a high speed and carry acute pain (at the onset of pain). C-fibers are non-myelinated and carry chronic pain sensation at a slow speed. AB- fibers do not carry pain sensation.
The sensory nerve cells are located in the dorsal root ganglia. The axons carry pain to the cell body, the short fibers called dendrites enter the spinal cord and cross the midline and synapse with the 2 nd order neuron. From here the fibers run upwards as the lateral spinothalamic tract and synapse with dorsomedial nerve cells of the thalamus. The 3rd neuron carries the sensation to the Parietal Lobe of the cerebral cortex.
This set of nerve cells and nerve fibers carries pain sensation from the skin of one side of the body to the opposite cerebral cortex.
Mechanism of pain activation.
The free nerve endings in the skin are covered by a plasma membrane, which contains channels. Protein molecules open the channels when an appropriate stimulus is received and allow calcium and sodium ions to enter. This ions influx generates an electrical impulse that is carried to the dorsal root ganglion by the nerve fibers.
Pain sensation from Internal Organs.
The efferent fibers of the autonomic nervous system carry pain sensation. The vegus nerve carries visceral sensation to the Nucleus Tractus Solitarius of vagus. From there, pain sensation is relayed to the thalamus and also to the Hypothalamus and finally to the sensory cerebral cortex. Visceral pain is also carried by efferent fibers of the sympathetic system, the nerve body lies in the sympathetic chain and the pain is relayed to the Hypothalamus and finally to the cerebral cortex. Visceral pain is felt on the skin over the dermatome that corresponds to the origin of the viscera. However, those organs have a serous covering - Peritoneum, Pleura, or Pericardium, which is supplied by the spinal nerves, are very sensitive to pain and the pain is localized precisely. The pain is activated when the inflammatory process, following injury or infection, reaches the serous membrane.
Neurotransmitters of Pain.
Glutamate.
Glutamate is the main neurotransmitter for pain sensation of the dorsal root ganglia and many areas of the brain.
Substance P.
Substance P transmits Chronic pain. It is a polypeptide, made up of 11 aminoacids.
Glycrine dampens pain transmission at the Dorsal Root Ganglia.
In addition, many other neurotransmitters participate in the propagation of pain sensation and may act as suppressor or accentuator.
Common Terms used in this article.
Nociception Pain. When tissue injury or inflammation initiates the pain sensation, it is called Nociception Pain. The Pain in anticipation of such tissue damage, is also called nociception pain.
Somatic pain sensation. When pain is felt from the skin, subcutaneous tissue and muscles, tendons and bones.
Visceral pain. Pain originates from solid or hollow viscera. Pain is felt as painful cramps and squeezing pain.
Inflammatory pain. Tissue damage releases various cytokines locally, which trigger pain sensation.
Neuropathic Pain. When nerve cells or nerve fibers are damaged from systemic illness or injuries, the pain is felt as unpleasant or burning pain. It is common in Diabetes mellitus and certain chemotherapeutic agents.
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A few well accepted views.
Females are more sensitive to pain than men. Older generations are less sensitive and react slowly to pain. There are cultural and social variations for tolerance of pain. Certain professions teach their recruits to tolerate pain, e.g, military base camp training. When life itself is at risk, painful injuries are ignored and people with severe painful wounds walk away from the site of the accident/incident.
Pain is highly subjective. The pain is graded differently by different people when asked to grade the pain on a 1 to 10 scale. MRI scan of the brain and PET scan are known instruments that correlate the patient's story of pain. But a physician must not distrust his/her patients; in case a physician has doubts, the physician should remove himself/herself from taking care of the patient. It is not ethical nor cost-effective to obtain an MRI to verify the patient's story of the chronicity or severity of the pain.
Processing pain at different levels of the nervous system differently.
At spinal cord level.
The spinal reflex arc.
The spinal nerve carrying pain sensation enters the spinal cord, at each segmental level, via the posterior root and synapses directly with the anterior horn cells of that segment and also up and down segments of the spinal cord. The muscles contract reflexly and remove the body part from the site that had caused pain. Conscious recognition of pain is achieved a few milliseconds later. In newborn children, the withdrawal reflex has not developed, they cry instead.
Nerve tracts carrying pain to the midbrain.
Spinothalamic tract. Connect with Thalamus. Function: localization of pain
Spino-reticular tract. Connect with the reticular formation of the mid brain. Function: produce awareness and arousal.
Spino-tactal tract. Connect with Tectum. Function – directs eyes and head towards the pain sensation.
In the midbrain.
The Thalamus is the initial reception center of Pain and in fact, all other sensory impulses carried by the spinothalamic tract end here. It is called a crude sensory center, meaning, pain is registered here without any other qualification – as to the severity, precise location and the cause. Different areas of the cerebral cortex, nearly all mid brain nuclei, the hypothalamus, the amygdala and the hippocampus are connected two ways with the thalamus via synapses.
In an embolic stroke of the hypothalamus, the pain is felt as an unrelenting burning sensation.
In the cerebral cortex.
In the Parietal lobe of the brain, the pain sensation reaches the conscious level. The parietal lobe is stratified - a specific location is designated for pain arriving for a specific area of the body. Face, lips and fingers of the hand have much wider cortical representations than the body parts occupy. In simple terms, it means these areas are more sensitive than the trunk and the proximal parts of limbs.
In the last several years, experiments with pain localization and perception have expanded knowledge of the participation of other areas of cerebral cortex. Several new synaptic connections with the thalamus and the hypothalamus have contributed to the understanding of pain perception and how that relates to addiction to pain medication.
Recent additional areas of the brain involved in pain perception.
Anterior part of Cingular Gyrus.
The Cingular gyrus used to be part of the Limbic system. Recent functional MRI and PET scans have conclusively proved the anterior part of the cingulate gyrus modifies pain sensation. Additional areas are the Insular cortex, the ventromedial Orbital cortex, and the Motor cortex
Current understanding of Pain Discrimination and Pain Perception.
There are two parallel systems at work. The components of the Lateral system are sensory, the Parietal cortex 1 and 2, the thalamus, and the lateral spinothalamic tract. The main function of this system is to bring the pain sensation to the conscious level and define severity, localize and make a logical conclusion of the origination of pain. This aspect of sensation is involved in pain discrimination.
The Medial system consists of the Anterior Cingulate gyrus, the insula, the motor cortex and the spinoraticular tract with all the synaptic connections as shown in the diagram. This part of the system analyzes, recalls, recalibrates and interprets pain. This part of the system is involved in pain perception.
Pain Receptors of the Central Nervous System:
Opioid Receptors.
A. Opioid receptors have a vital role in pain modulation and anti-nociception. Opioid receptors are further classified into three types.
1. Delta receptors are situated in both the brain and the spinal cord sensory neurons and are involved both in pain and depressive illness.
Kappa receptors are situated in the grey matter of the spinal cord and hypothalamus, and have a vital role in the treatment of pain, stress and depression-like conditions.3.
Mu receptors are situated in the intestine, spinal cord, cortex and thalamus of the brain. All Mu receptors have a primary role in analgesia, but Mu1 receptors are particularly involved in the perception of pain.
Opioid drugs act on opioid receptors and attenuate pain by hyperpolarization. It is mediated by the opening of potassium channels and the closing of calcium and sodium channels. Opioid drugs block the adenylyl cyclase enzyme also.
Fentanyl, Morphine and Methadone are important members of opioid drugs. Opioid blockers are Naltrexone and Naloxone.
B. Dopamine Receptors.
There are five sub-varieties of Dopamine receptors - D1 to D5.
D1 receptors are excitatory in nature. D2, D3 and D4 receptors are all inhibitory. They block the adenylyl cyclase enzyme..
Tergoride, Apomorphine, and Bromocryptine are activators of D1 receptors, Ecopipam works on D1 and D5 receptors and is a receptor blocker.
Haloperidol, Resperidone, Domepridone, block D2, D3 and D4 receptors. Apomorphine, Pramipexole, Bromocryptine, Cabergoline act as agonists of D2 receptors. Activation of D2, D3 and D4 receptors produces an analgesic effect.
C. Adrenergic Receptors.
Adrenergic receptors are further divided into two types - alpha receptors and beta receptors.
Alpha-adrenergic receptors have two important sub-types – alpha-1, and alpha-2.
Alpha-1 has an excitatory effect, while alpha-2 has a role in the release of norepinephrine.
Beta receptors have three important sub-types - beta-1, beta-2 and beta-3.
Beta-1 receptors are involved in stimulatory responses, while beta-2 and beta-3 have a major role in inhibitory responses. All alpha receptors have a role in the blood vessel constriction and a reduction in gastric emptying.
Drugs having a stimulating effect on alpha 1 receptors – Tamsulosin, Terazosin, and Prazosin. Alpha blocker drugs are Mirtazapine and Yohimbine
Alpha 2 stimulating drugs are Methyl-dopa, Clonidine and Guanabenz
Pain sensation occurs at different levels of the peripheral nerves, the spinal cord and the brain. Although great strides have been made in recent years, the pathology of Pain perception is not fully understood.
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