Pain Physiology PDF

PAIN PHYSIOLOGY Prof. Dr. Lamia Pınar İstanbul Okan University Medical Faculty Dpartment of Physiology OBJECTIVES After studying this chapter, you should be able to: Describe the receptors that mediate the sensations of pain and temperature Explain the differences between pain and nociception, first...

PAIN PHYSIOLOGY Prof. Dr. Lamia Pınar İstanbul Okan University Medical Faculty Dpartment of Physiology OBJECTIVES After studying this chapter, you should be able to: Describe the receptors that mediate the sensations of pain and temperature Explain the differences between pain and nociception, first and second pain, acute and chronic pain, hyperalgesia, and allodynia. Describe and explain visceral and referred pain Describe processes involved in the modulation of transmission in pain pathways. Relief of pain Pain or Nociception; is a protective mechanism. It provides a reflex activity to withdraw the parts of the body from a harmful object or alert the brain. Fast pain, also called acute pain or physiological pain, is transmitted to the central nervous system by thin myelinated A delta (Aδ) fibers. Fast pain, mostly occurs in the skin and underlying tissues by chemical, thermal, mechanical, or polymodal (all of them) stimuli. It is felt as burning, pinprick, knife wounded, electric shock, etc. It is sharp, and intense pain. It can be localized and recognized by its sharpness and intensity. Slow pain (pathological pain) usually occurs due to tissue damage It is transmitted to the central nervous system by thin unmyelinated C fibers. It can create an unbearable feeling when it prolonges, even if its intensity is not very high. Slow pain is also called chronic or visceral pain because it is generally produced by inflammation, infection, or stretching of the visceral organs or damage to the deep tissues such as joints. The pathway of chronic pain activates the reticular activating system (RAS) in the brainstem and causes the brain to become alert about the matter. Pain Receptors: (NOCICEPTORS) For both acute and chronic pain, the receptors are ‘Free Nerve Endings’ (or naked nerve endings) Pain receptors are called nociceptors. They are located in the skin, subcutaneous and deep tissues, and in the visceral organs Acute pain fiber’s neurotransmitter is Glutamate Chronic pain fiber’s neurotransmitter is Substance P (Lewis' P factor) After a tissue injury; inflammation occurs in the area The main symptoms of the inflammation (flare) are, - Redness, - Fever - Swelling - Pain Both fast and slow pain systems travel to the CNS by Lateral Spinothalamic pathways (in the Antero-Lateral System) Fast Pain Slow Pain Sharp, pricking Dull, burning Thin myelinated (A) fiber Group IV (C) fiber Short latency Slower onset Well localized Diffuse Short duration Long duration Less emotional Emotional (may be agonizing) Not blocked by morphine Blocked by morphine Neospinothalamic Tract Paleospinothalamic Tract Muscle Pain The contractions of an ischemic muscle cause pain even in a short time. Because contracting muscle produces metabolites such as Lewis’ P factor (substance P). The P factor may be potassium. When the blood supply is restored, the pain disappears. Pain produces muscle spasms. This mechanism resembles the flexion reflex of muscles due to pain. Acute abdomen is referred to as abdominal muscle spasms caused by the pain of inflamed organs in the abdominal or pelvic cavity (such as inflammation of the appendix). Clinically, substernal pain develops when the myocardium becomes ischemic during exertion. It is called angina pectoris. Resting, relieves angina by decreasing the heart load and O2 requirement. The 1st neurons of acute and chronic pain fibers are in the spinal ganglion. Afferents enter the spinal cord through the dorsal root and come to the dorsal horn. In the dorsal horn, they synapse with their second-order neurons. Some of the axons of 2. neuron produce reflex activity at the same side (ipsilateral). Some pass to the other side of the spinal cord and ascend to the upper brain areas. Transmission of pain fibers to the CNS Pain Induced Withdrawal Reflex When we touch our limb to a painful object, we pull it back by flexion reflex. Likewise, in the lesion of internal organs, abdominal flexors contract and produce spasms (Acute abdomen). Visceral Pain Visceral pain (internal organs’ pain) can be associated with autonomic symptoms like nausea, sweating, or changes in blood pressure. There are no proprioceptors, temperature, or touch receptors in the internal organs, so we cannot feel their location. Pain receptors in the internal organs are less and distributed sparsely. Pain and the other sensory fibers from visceral structures are carried to the CNS via sympathetic and parasympathetic afferent pathways. After a tissue damage on the skin or deeper areas, inflammatory factors like bradykinin, potassium, histamine, acids, leukotrienes, prostaglandins, nitric oxide (NO) and calcitonin gene-related peptides (CGRP) can increase sensitivity which causes pain in the inflammatory area. The acute pain fiber’s neurotransmitter is glutamate, and the chronic pain fiber’s neurotransmitter is substance P. Referred Pain Mostly the internal organs’ pain is referred the somatic structures of the body. The reason is the brain doesn’t know about the internal organs because there are no proprioceptors, touch and thermal receptors in the internal organs. There are two hypotheses to explain this mechanism; During embryonic development, some of the internal and somatic organs arise from the same segments of the neural tube and obtain their sensory nerves from these segments. 1- The visceral pain fibers enter the spinal cord and make synapses on the same second neurons (mutual) with the fibers coming from the somatic areas. Then, both visceral and somatic fibers ascend to the brain. However, because the brain does not recognize internal organs, it assumes that the pain sensation is coming from the somatic area. 2- Maybe there are separate 2. order neurons for visceral and somatic pain fibers. But the relationship between them also activates the somatic 2. order neurons. Again, the brain assumes that the pain is coming from the somatic area of the body. The most painful areas of the body Periosteum of the bones Membranes around and in the brain (meninges, falx cerebri, tentorium cerebelli) The walls of the great arteries Lung and liver capsule Skin and muscles In contrast, brain, lung, and liver parenchymal tissues are insensitive to pain. Cold and Heat-Sensitive Pain Receptors Cold sensation is mostly carried to the upper systems in the acute pain pathways by A-δ fibers. Heat is carried together with the chronic pain pathways, by the C fibers Extreme heat > 45ºC and extreme cold < 10ºC activate pain receptors Recently, it was recognized that some vanillins (vanilya), and capsaicin (found in the red pepper) also cause pain. The potentials that act on vanilloid receptors are called “transient receptor potentials, TRP”, there are TRPV1, TRPV2.…TRP8 type receptors. TRP causes to open some ion channels, such as Na+, Ca2+, Mg2+ Normal (moderate) cold receptors are sensitive to cold between 10-24oC and are called as cold-and menthol-sensitive receptors (CMR1) or (TRPM8).Temperatures below 10οC, towards minus degrees initially cause pain and then have an anesthetized effect. Analgesic Substances Opiate Peptides The most prominent analgesic substance for pain is morphine. Fortunately, the body can produce its own morphine-like substances and try to suppress the pain. Endogenous morphine-like substances are opioid peptides Opiates are enkephalins, endorphins, and dynorphins. They can be referred to as leu-enkephalin, met-enkephalin, dynorphin and endorphin. Analgesia-related Enkephalinergic neurons are found in three areas 1- Enkephalin is released from the immune cells in the inflammatory (injured) area. 2- They are released from the enkephalinergic neurons in the dorsal horn to suppress pain impulses coming from peripheral afferents (gate-control system). 3- They are found around the periventricular area and periaqueductal gray matter. The periventricular area and periaqueductal gray matter in the brainstem are the centers of emotions such as pain, grief, agony, misery and soreness, distress, heartache, and desperation (punishment center). Excessive pain or emotional shock causes the release of enkephalin from the vicinity cells to compensate for the agony. Cannabinoids in Pain Relief Cannabinoids are psychoactive compounds found in marijuana. At low (pharmacological) doses, cannabis can cause calmness and relaxation, reduction of pain, increase of appetite, but also decrease of shortterm memory. But it can be addictive. In high doses, it causes personality changes, hallucinations, and even delirium. Recently, some forms of cannabis have been approved for limited medical use primarily to treat nausea and stimulate appetite, in some cancer patients. There are also endogenous cannabinoids called anandamide (arachidonic acid derivative) in the brain. They produce stress-induced analgesia Pain Suppression in the Brain and Spinal Cord Putting one’s hand into water at 45oC will produce pain in everybody However, Reaction to this pain occurs differently, although the pain threshold is the same for all humans. Some people can use the suppression system of their brain but, others activate the central excitation system (CGRP) of their brain. To endure pain and other sensory impulses depends on the use of the brain’s suppressor effects. There are some sensory descending pathways from the brain to the spinal cord. These pathways may inhibit the pain fibers entering the spinal cord to some extent by causing presynaptic inhibition. Sensitization of the pain by the effects of CNS (CGRP) Gate-control mechanism in pain inhibition (1) Descending Analgesic Systems When there is unbearable pain or severe emotional shock, the brain’s opiate system is activated. The axons of the enkephalinergic neurons in the brainstem activate the serotonergic neurons in the Nucleus Raphe Magnus in the brainstem. The axons of the serotonergic neurons descend to the spinal cord and activate the enkephalinergic neurons in the dorsal horn (in the Substantia Gelatinosa of Rolando). The pain-carrying fibers are presynaptically inhibited by these enkephalinergic axons to some extent. Thus, the pain impulses are inhibited before they reach the upper levels of the brain where they would be perceived. This is the ‘gate-control mechanism of pain inhibition’ (Corticofugal Pathway). Enkephalin and endorphin systems can also be activated by the brain cortex*. *People who have self-control (willpower) can manage his/her pain to some extent. Presynaptic Inhibition; is the reduction of presynaptic and postsynaptic depolarization by the effect of a GABAergic neuron that makes an axoaxonal connection to the presynaptic end. In the Gate-Control Mechanism of pain; the enkephalinergic neurons in the dorsal horn (substantia gelatinosa) activate the GABAergic interneurons. These in turn, by presynaptic inhibition, decreases the pain fibers depolarization. Thus, calcium entering the presynaptic cell decreases and the neurotransmitter release also decreases. So, the postsynaptic neuron (the 2ndorder neuron of the pain) cannot be activated. Defense System Developed by the Brain in Physical and Emotional Trauma We see that although the periventricular and the periaqueductal areas in the brainstem and hypothalamus are concerned with punishment, fear, rage, and terror sensations, the stimulation of some neurons here can also initiate a compensatory mechanism to prevent the subject from dying due to pain shock. Sometimes, the pain or emotional shock is so severe that the excess release of endorphins, and enkephalins together with the release of corticosteroids can shut down the mind and lead to unconsciousness as is seen during big accidents, disasters, or war wounding. Pain inhibition by touching, pressure, rubbing, electrical stimulation, acupuncture applications GATE CONTROL SYSTEM Another physiological method of pain relief is to rub, shake, or electrically stimulate the painful part of the body. Doing so may activate the touch or proprioceptive pathways (Dorsal Column-Medial Lemniscal System). These pathways, give some collaterals and activate inhibitory interneurons, which can create lateral inhibition and cause pain relief. It is thought that pain relief by acupuncture depends on this method. Pain Pathways and Pathophysilogy Somatic Sensations are transmitted to the upper brain areas by way of ; Dorsal column-medial lemniscal system (proprioceptive, fine touch, fine pressure vibration)) Anterolateral System (pain, thermal, crude touch, and crude pressure) - pain and thermal senses by lateral spinothalamic pathway - crude touch, pressure, and unimportant senses by anterior (ventral) spinothalamic pathways Spinothalamic Pathway of Chronic Pain Chronic pain fibers coming from the deep tissues or visceral organs, follow the acute pain pathways. But; Most chronic pain fibers relay on the brainstem (reticular formation) and activate RAS. Then, project to the centrolateral nucleus of the thalamus for 3. neuron From the thalamus, they end in their 4. neuron in the postcentral gyrus of the cortex. PET and fMRI studies in humans indicate that chronic pain activates the primary and secondary somatosensory cortex, the cingulate gyrus, amygdala, frontal lob, and the insular cortex on the side opposite of the stimulus. Thus, these pathways mediate the affective component (suffering, agony) of pain Visceral sensation travels along the same pathways as the somatic sensation or with the cranial nerves and after relaying on limbic areas (especially to the hypothalamus) they intermix in the sensory cortex. Acute and Chronic Pain fibers along the lateral spinothalamic tract NOT: some pain fibers after synapsing with the 2. order neurons, produce flexion reflex at the same side (ipsilateral) This data is not shown in this figure The sensation of the face is perceived by Trigeminal Nerve (5. Cr) The trigeminal nerve (the fifth cranial nerve) is responsible for facial sensation and motor functions such as biting and chewing. It has 3 main branches: 1- Ophthalmic nerve (sensory) 2- Maxillary nerve (sensory) 3- Mandibular nerve (motor + sensory) The ophthalmic and maxillary nerves are purely sensory, whereas the mandibular nerve supplies motor as well as sensory (or "cutaneous") functions. The 7.Cr nerve : The facial nerve has motor function of the face, but some axons get senses from the tongue and salivary glands CLINIC Damage to pain pathways produces a deficit in pain and temperature discrimination and may also have abnormal, painful sensations called dysesthesia. In some inflammatory diseases of pain fibers, any stimulus that would generally cause only minor pain produces an exaggerated response called hyperalgesia,and an innocuous stimulus such as touch which causes pain, is called allodynia. Neuropathic pain Neuropathic pain is characterized by a burning, tingling, stabbing, or electric shock-like quality. Frequently it includes burning or coldness, pins and needles (tingling) numbness, and itching. It is mainly seen in diabetic patients. It does not even respond to non-steroid anti-inflammatory drugs (NSAIDs). In some neuropathic pain lesions ‘reflex sympathetic dystrophy, RSD’ can be seen. Trigeminal Neuralgia (tic douloureux) - excruciating (dayanılmaz), episodic pain in the area supplied by the trigeminal nerve, - intense pain makes the patient grimace (tic) - antiepileptic drug (phenytoin, carbamazepine) can be used, or, - surgical treatment is effective Thalamic Pain Syndrome (Dejerine–Roussy syndrome) It occurs as a result of a lesion in the thalamus (ischemia, bleeding (hemorrhage, tumor), It occurs in the relevant areas and related sensations. It starts with numbness, tingling, and dysesthesia. It progresses with a burning sensation, hyperalgesia, and allodynia Patients report that any stimulus that does not cause pain, even a sound or taste causes severe pain. Symptoms are unilateral, depending on the affected areas of the thalamus. It can even impair vision and balance. Low of Projection in Sensory System Phantom Pain Phantom Feeling (or phantom pain); is a sensation coming from the amputated organs or tissues. Its mechanism is not known very well. However, it is supposed that it might depend on the sensory coding of the previous pain sensation in the sensory cortex due to neural plasticity. That engram can be activated by any stimulus, coming from vicinity areas of the body. Pain-based learning occurs in the spinal cord posterior horns, thalamus, or sensory cortex by Neural Plasticity mechanisms. Syringomyelia is a chronic progressive disease in which longitudinal cavities (syrinx) form in the cervical region of the spinal cord. This characteristically results in the weakening of the muscles in the hands and bilateral loss of pain and temperature sensation. Syringomyelia initial symptom - bilateral loss of pain and temperature sensation and paralysis. Herpes zoster: shingles Chickenpox virus causes this infection. It is taken by the peripheral nerves and carried to the spinal ganglia (by retrograde transport). When the virus infects nerves (namely, the dorsal root ganglia), it remains for years in the body to be activated whenever the immune system of the body weakens. It can then be reactivated to cause shingles with blisters over the distribution area of the affected nerve accompanied by often intense pain and itching.