Mechanisms of Pain PDF

[email protected] Wolfson CARD Guy’s Campus Dr. Kirsty Bannister Pharmacology and Therapeutics Mechanisms of Pain Learning outcomes Lecture Aims l To review the underlying mechanisms of pain Learning Outcomes By the end of the lecture you should be able to:l l l Describe pain in terms of se...

[email protected] Wolfson CARD Guy’s Campus Dr. Kirsty Bannister Pharmacology and Therapeutics Mechanisms of Pain Learning outcomes Lecture Aims l To review the underlying mechanisms of pain Learning Outcomes By the end of the lecture you should be able to:l l l Describe pain in terms of sensory discriminative and affective motivational dimensions Understand the basic process of nociception to include transduction, transmission, modulation and perception Recall the fundamental differences between acute and chronic pain, with mechanistic understanding of 3 pain types Pain is UNIQUE An unpleasant Sharp Stabbing Burning Piercing SENSORY Sensory aspects of pain Unpleasant uncomfortable excruciating and EMOTIONAL Psychological aspects of pain experience associated with, or resembling that Affective motivational: unpleasant, Sensory discriminative: threshold, associated tissueaversive threatening, intensity and locationwith, actual or potential damage ‘’On a scale of 1-10 how intense is your pain?’’ ‘’On a scale of 1-10 how unpleasant is your pain?’’ Basic pain processing pathway Limbic brain Affective aspects of pain Fear, anxiety, sleep Mid brain top-down processes control pain perception CORTEX Location and intensity DESCENDING CONTROLS Spinal Cord Incoming peripheral nerves Convey touch/temp.. Integrates, amplifies and modifies incoming messages: output to the brain The ability to feel pain: Nociception Nociception is the neural process of encoding noxious stimuli: a sensitivity to a noxious ‘tissue-damaging’ stimulus or to a stimulus that would become noxious if prolonged Physiologically composed of 4 processes: ❖ TRANSDUCTION ❖ TRANSMISSION ❖ MODULATION ❖ PERCEPTION The process of pain TRANSDUCTION NOCICEPTORS ❖ On nociceptors are sensory receptors that respond to noxious stimuli and transduce them into receptor potentials ❖ may give rise to the perception of pain ❖ A𝛅 and C fibres are polymodal nociceptors Free nerve endings may respond to: Mechanical, thermal, or chemical painful inputs (can be polymodal) The process of pain TRANSMISSION The relay functions by which the message is carried from the site of tissue injury to the brain regions underlying perception The nociceptive message is transmitted from the Transmission from PNS to CNS periphery to the CNS by the axon of the primary afferent nociceptor Primary afferents release chemical transmitters (substance P, glutamate etc) from their terminals (TRANSDUCTION)… …which activate second order neurons as the ‘message’ travels via DRG to the dorsal horn via sodium and calcium channels (TRANSMISSION) There can be pain without transmission in the primary afferent and there can be activity in a primary afferent without pain; there is a variable relationship between nociceptor input and perceived pain intensity The process of pain TRANSMISSION Once transduced and generated, action potentials are conducted to the central nervous system via C fibre and A delta primary afferents ❑The primary afferent nociceptor contacts second order pain transmission neurons in the spinal cord ❑Second order cells relay the message through well defined pathways to higher brain centres including the brain stem reticular formation, thalamus, somatosensory cortex and limbic system The process of pain MODULATION Modulation is a neural process that acts specifically to alter activity in the transmission system Descending pain modulatory system Comprising….. Periaqueductal Grey Locus Coereleus Rostral Ventralmedial Medulla …projections to the dorsal horn of the spinal cord The process of pain MODULATION HOW DO DESCENDING CONTROL PATHWAYS EXERT POWERFUL CONTROLS OVER SPINAL NEURONAL PROCESSES? Descending noradrenergic projections arise almost entirely from LC regions: INHIBITORY Descending serotonergic projections arise almost entirely from RVM regions: FACILITATORY AND INHIBITORY Acute versus chronic pain ACUTE PAIN IS…. GOOD!!!! ✓ ✓ ✓ ✓ Evolutionary advantage A discrete biological purpose Self limited Associated with tissue damage after surgery CHRONIC PAIN IS…. BAD!!!! ✓ Considered a disease state ✓ Pain outlasts the normal time of healing (if associated with disease or injury) ✓ May arise from psychological states serving no biological purpose Why does pain become chronic? Peripheral Sensitisation An increased sensitivity to an afferent nerve stimulation Peripheral sensitisation produces an increased pain response due to nociceptors producing lots of neuropeptides ✓ Primary hyperalgesia ✓ Allodynia ✓ Upregulation of existing receptors ✓ Upregulation of new receptors ▪ A reduction in threshold ▪ An increase in the magnitude of responsiveness of sensory nerve endings Why does pain become chronic? Central Sensitisation Amplification of pain by central nervous system mechanisms ❖ Not defined by activation of a single molecular pathway but rather represents the altered functional status of nociceptive neurons ❖ Mechanisms can be driven by different molecular effectors including the kinases ❖ These kinases participate in changes in threshold and activation kinetics of AMPA and NMDA receptors and their trafficking to the membrane PS vs CS: summary Peripheral Sensitisation Represents a reduction in threshold and an amplification of responsiveness of nociceptors that occurs when peripheral terminals of these high-threshold primary sensory neurons are exposed to inflammatory mediators – as a consequence pain is restricted to the site of injury. Central Sensitisation In contrast co-opts novel inputs to nociceptive pathways including those that do not normally drive them ie Abeta fibre mediated pain. It produces pain sensitivity long after the initiating cause and when no peripheral pathophysiology is present – an abnormal state of responsiveness. Different types of pain Pain can be characterised as: Inflammatory: Painful symptoms associated with an inflammatory response Neuropathic: Pain caused by a lesion or dysfunction of the nervous system Central: Pain caused by a lesion or dysfunction of the central NS Mechanisms in inflammation Eicosanoids include: Aspirin NSAIDs COX-1 COX-2 Leukotrienes Thromboxanes Prostacyclin ❖ Leukotrienes, Lipoxins, Thromboxanes, Prostanoids ❖ They have important roles in inflammatory responses Prostaglandins PGE2 and PGI2 are usually regarded as the most important eicosanoids with respect to the pain producing or enhancing aspects of inflammation. These compounds are generally thought of as ‘enhancers’ rather than ‘producers’ of pain. Mechanisms in inflammation Noxious factors will ✓ increase the activity of sensory neurone specific VG Na channels ✓ Reduce activity of VG K channels Leading to depolarisation and excitation of nociceptors Mechanisms in neuropathy Neuropathic pain is generated as a result of a disease or lesion that causes nerve injury Surgical trauma: nerve laceration Since there is a loss of afferent input it would be natural to assume that we would only experience numbness IN REALITY…. Patients now experience pain Whilst tissue heals reasonably quickly and efficiently nerves have a very limited capacity to fix themselves and thus neuropathic pain is often chronic Learning outcomes Lecture Aims l To review the underlying mechanisms of pain Learning Outcomes By the end of the lecture you should be able to:l l l Describe pain in terms of sensory discriminative and affective motivational dimensions Understand the basic process of nociception to include transduction, transmission, modulation and perception Recall the fundamental differences between acute and chronic pain, with mechanistic understanding of 3 pain types