Pain Mechanisms PDF

Pain PH5208 Dr. Moira Jenkins Pain 1. Transmission- lateral spinothalamic tract (pain and temperature) to VPL of thalamus → postcentral gyrus/analyze, cingulate gyrus/emotions, insular cortex/autonomic response, reticular formation and intralaminar thalamus/all areas of cortex 2. Perception 3. Mo...

Pain PH5208 Dr. Moira Jenkins Pain 1. Transmission- lateral spinothalamic tract (pain and temperature) to VPL of thalamus → postcentral gyrus/analyze, cingulate gyrus/emotions, insular cortex/autonomic response, reticular formation and intralaminar thalamus/all areas of cortex 2. Perception 3. Modulation- interneurons in CNS descending analgesic system Congenital insensitivity to pain, student at McGill University in Montreal in the 1950’s “Miss C” Normal in every way except she could not feel pain Bit off part of her tongue as a child, 3rd degree burns from kneeling on a radiator. Miss C. died at the age of twenty-nine of massive infections … and extensive skin and bone trauma. (this article was much later, New York Times Magazine) Individuals congenitally insensitive to pain are easily injured and most of them die at an early age. Terminology Associated with Pain • • • • • • • • • • • • • • Algesic=pain Analgesic – Pain relief or decrease Hyperalgesia – threshold for pain is lowered, hypersensitivity Hypoalgesia – threshold for pain is increased, hyposensitivity Allodynia- pain due to a stimulus that normally does not provoke pain Central pain –cause is within the central nervous system Neurogenic pain – cause is neural tissue, PNS or CNS Nociceptive pain- primary cause is nociceptive firing (rather than neural tissue lesion) Neuralgia – pain along the distribution of a nerve, usually sharp, electric Neuritis – inflammation of a nerve Neuropathy – damage of a nerve Radiculitis – inflammation of a nerve root, pain along nerve root Radiculopathy – damage of a nerve root, pain AND sensory/motor changes Referred pain- pain is felt/perceived in an area other than the pain generator Pain Mechanisms Nociceptors fire as a result of mechanical, thermal, or chemical stimulation Chemicals are released from damaged tissue IL-1 IL-6 TNF ATP Lactic Acid Prostoglandins Arachadonic Acid Stimulate nociceptors to fire→ Spinothalamic tract Spinotectal tract Reflexive somatic and visceral responses Pain Mechanisms There does NOT have to be tissue damage for pain mechanisms to be activated Typical diet can do it IL-1 IL-6 TNF Lactic Acid Prostoglandins Arachadonic Acid Stimulates NFKappa B, an inflammatory signaling cascade that causes the cells to secrete chemicals that stimulate nociceptors Some sensory receptors can be modulated/change their sensitivity Ex: press upon a mechanoreceptor with a set amount of force – this receptor normally responds to that amount of force by signaling at 10 Hz … • if the response is now a greater signal (14 Hz) with the same force → increased sensitivity • if the response is now a lesser signal (7 Hz) with the same force → decreased sensitivity This can occur with nociceptors Hyperalgesia and hypoalgesia refer to an altered sensitivity of nociceptors hyperalgesia → sensitization (an increase in the sensitivity) • two outcomes: − a perception that a given stimulus is more painful than usual, and … − what is normally a non-noxious stimulus may now be perceived as painful (in effect, the stimulus threshold has been reduced) ALLODYNIA hypoalgesia (analgesia) → desensitization (a reduction in the sensitivity) • two outcomes: − a perception that a given stimulus is less painful than usual, and … − what is normally a noxious stimulus may now be perceived as non-painful (in effect, the stimulus threshold has been elevated) → hyperalgesia or hypoalgesia may arise from altered receptor sensitivity, or from modulation of neurotransmission at the first synaptic relay within the dorsal horn of the spine • primary: a change in the peripheral receptor sensitivity to a given stimulus • secondary: a change in the strength of synaptic transmission of peripheral afferent signals arising from the nociceptors to the second order relay neurons Physiological Processes That Enhance Pain and May Lead to Chronicity (pain lasting more than 3-6 months) • Sensitization (repeated stimuli leads to thresholds decreasing), hyperalgesia, allodynia • Hyperactivity of the sympathetic nervous system, can activate nociceptors or restrict blood flow to tissue • Activation of latent secondary neurons from constant nociceptive input Sensitization • Injured cells may release various chemical substances into the local tissue space that will sensitize nociceptors • Released chemicals that sensitize adjacent nociceptors include K+, bradykinin, histamine, serotonin, leukotrienes, prostaglandins, cytokines, and substance P • Released chemicals may directly activate nociceptors: H+, serotonin, bradykinin, histamine released neuropeptides such as substance P and CGRP may also stimulate inflammation → neurogenic inflammation see also: Kandel & Schwartz Figs. 24-8 & 9 Neurogenic Inflammation Activated nociceptors may also release neuropeptides into the local tissue space that can sensitize and/or activate surrounding nociceptors, e.g. substance P and calcitonin gene-related peptide (CGRP) **Nociceptors – can both release and be activated by inflammatory chemistry Ex: Substance P Fiber Types IV, C nociceptors III, A delta nociceptors II, A beta I, A alpha mechanoreceptors mechanoreceptors All the sensory fibers report to the dorsal horn or to the brainstem nuclei Stimulation of mechanoreceptors through skin, massage, acupuncture, physiotherapies, Manipulation (Fast fibers and great stimulation with high velocity movement) Nociceptors have a higher stimulus threshold, compared to non-nociceptive receptors → a greater stimulus intensity is therefore required to initiate signaling from nociceptors nociceptive signaling is conveyed from the periphery into the CNS via Ad and C fibers • Ad fibers arise from mechanical and thermal nociceptors; convey sharp (short lasting) sensation of pain • C fibers arise from polymodal receptors; convey dull or diffuse pain e.g. in response to a painful stimulus: • an initial sharp pain is conveyed by Ad fibers → “first pain” • a longer duration, duller sensation of pain is subsequently conveyed by C fibers → “second pain” Kandel & Schwartz Fig. 24-1 2 classes of nociceptors (A and C fibers) leads to “Double” Pain Phenomenon Two sequential pain sensations in short time intervals is the result of sudden painful stimulation. First one is immediately after the damage, followed several seconds later with additional pain sensation. These two separate sensations are several seconds apart because a fast transmitting information sensation is carried via A delta fibers and is followed several seconds later with slow transmitting pain information carried via C fibers. Gate Control Theory of Pain non-noxious input [stimulation] suppresses pain). Spinal transmission: The gate control theory of pain modulation 2nd-order relay a “gate control” inhibitory interneuron (within the gray matter of the dorsal horn) synapses upon the 2nd order neuron • this inhibitory interneuron restrains feedforward transmission of the nociceptive stimulus through this relay two different inputs 1. the gate control interneuron is inhibited via C-fiber activity → uninhibited transmission of the nociceptive input 2. non-noxious input via myelinated Ab fibers stimulate the gate control interneuron → inhibiting transmission of the nociceptive input through the relay neuron Stimulate a mechanoreceptor-can reduce the relay of nociception to the 2nd order neuron and modulate pain This form of analgesia will be effective for mildly painful stimuli; the signaling strength from more intense nociceptive stimulation will be too strong to overcome via these inhibitory interneurons see also: Kandel & Schwartz Fig. 24-14 What about Visceral pain? • • • • Visceral afferents have relatively few central projecting fibers and cover large receptive fields Vague, poorly localized Ascending tracts reports to several areas including limbic system May be perceived as somatic pain due to cross talk in the dorsal horn (referred pain) Sensation from Visceral Structures Unpleasant! •Ischemia •Inflammation •Distension/stretching •Cramping Referred Pain somatic sensory gray ONLY somatic sensory axons return here ? BOTH somatic and visceral sensory axons return here ? Referred Pain Referred Pain • Recall that somatosensory information is transmitted to the brain by labeled lines that preserve somatotopic mapping back to the receptive fields • Dermatome is a map of the skin supplied by a specific nerve root level • Visceral nociceptors and skin nociceptors can converge on same dorsal horn neuron • → Visceral stimuli may therefore be perceived as originating from a somatic site → our brain may then refer neural signaling arising from visceral receptors to a somatic location Referred Pain Due to the convergence of different afferents onto the same dorsal horn neurons in the spinal cord OR convergence of cranial nerves on the trigeminal nuclear complex. Referred pain is not always somatic to visceral, can be somatic to somatic, somatic to visceral Phantom Pain • Phantom or illusory pain is the experience of pain without any signals from nociceptors (relating to a limb or an organ that is not physically part of the body). • Common after a limb has been amputated or its sensory roots have been destroyed. Complex and not well understood. Possibly abnormal discharges 1) from remaining cut ends of nerves which grow into nodules called neuromas 2) from overactive spinal neurons 3) from abnormal flow of signals through the somatosensory cortex 4) from burst-firing neurons in the thalamus. Descending Inputs to Dorsal Horn Interneurons- Top Down Populations of inhibitory interneurons within the spinal cord may be stimulated by descending signals that originate from the brain Provides a means to selectively “sculpt” ascending sensory information from the dorsal horn into the brain Sculpt/suppressing other “background signals” that would be interpreted as “interfering noise” in order to “selectively focus attention” upon one particular source of sensory input Or inhibit incoming pain (Endogenous Analgesic System) Descending Pathways to Modulate Pain Endogenous Analgesic System Two descending pathways originate from: • periaqueductal gray matter • locus ceruleus Terminate via inhibitory synapses upon dorsal horn neurons • periaqueductal gray fibers are serotonergic • locus ceruleus fibers are noradrenergic Cramer & Darby Fig. 11.6 Opiod peptides from spinal inhibitory interneurons may block nociceptive transmission by two mechanisms • presynaptic inhibition-receptors on the presynaptic terminal of the primary afferent nociceptive fiber – stimulating the enkephalin receptor will hyperpolarize the membrane (via increased K+ conductance) – fewer Ca++ channels will open, and these will remain open for a shorter duration of time upon arrival of an action potential → reduced or blocked neurotransmitter release • postsynaptic inhibition, via receptors on the postsynaptic membrane – stimulating these postsynaptic opiod receptors will hyperpolarize the resting potential of the postsynaptic membrane – a subsequent EPSP will be less likely to reach a threshold for stimulating an action potential from the postsynaptic neuron Interneurons Modulate Information from Periphery to Brain- Bottom Up through dorsal horn Interactions Between Neurons Pain Mechanisms Stimulation of mechanoreceptors inhibits nociceptors, pathways, and pain reflexes Vagal tone, laughter, hobbies, singing, social interactions, etc can inhibit pain Diet and anti-inflammatory supplements Move patient’s out of acute pain asap Pain greater than 3-6 months → chronic Can still help break pain cycle