IM 12.3.1 Physiology of Pain 2024-2025 PDF

IM-12.3.1 Pain and Neuronal Plasticity Prof. Dr. Sandra Younan Professor of Physiology Kasr el Aini Faculty of Medicine Cairo University 2024-2025 Aim and Objectives Aim: To provide the medical student with a general understanding of pain and its control Objectives: By the end of this lect...

IM-12.3.1 Pain and Neuronal Plasticity Prof. Dr. Sandra Younan Professor of Physiology Kasr el Aini Faculty of Medicine Cairo University 2024-2025 Aim and Objectives Aim: To provide the medical student with a general understanding of pain and its control Objectives: By the end of this lecture you will be able to understand: Definition of pain, its affective and sensory dimensions Factors that can modulate (increase or decrease) pain experience Inflammatory and neuropathic pain Pain pathway (ascending and descending) Primary and central sensitization Hyperalgesia and allodynia Definition of Pain According to the International association for study of pain (Mersky,1979) ‘Pain is an unpleasant emotional and sensory experience associated with actual or potential tissue damage, or described in terms of such damage’ Pain is a symptom! Importance of pain Pain is protective Pain prevents damage from occurring The dimensions of pain Pain is described in terms of three dimensions: 1. Sensory Dimensions -Intensity, quality, location and duration 2. Primary Affective Dimension unpleasantness, distress, fear 3. Secondary Affective Dimension anxiety and depression What can downregulate the pain experience? Our expectations, mood and perspective on pain powerfully influence how much something actually hurts and the decision we make every day (Fields, 2009) Many factors can decrease the pain: 1. Pleasure 2. Stress 3. Placebo 4. Fear How? The body releases endogenous opiate peptides and cannabinoids Opiates is an older term that refers to drugs derived from opium, including morphine itself  1. Pleasure: Positively rewarding activities generate analgesia 1. In infants with tissue injury or inflammation, suckling and sucrose ingestion cause analgesia 2. Sucrose ingestion induces release of endogenous opioids which activate dopamine pathways to forebrain (‘reward pathways’) Fields, 2004  2. Stress-induced analgesia: Battel ground effects The anesthetic consultant, H.K. Beecher reported that following the Italian World war II: Anzio beachhead 1944, 70% seriously wounded did not require analgesics versus 70% of civilians with post- operative pain did! Stress is seen during Paralympic competitive games Stress analgesia is also seen in animals  Somatosensory cortex Somatosensory cortex is present in the postcentral gyrus of the lateral parietal lobe of the brain The primary somatosensory cortex contains a representation of the opposite side of the body Afferents from every body part send their information to a designated area of the somatosensory cortex The greater the cutaneous receptors of this body part, the larger is its brain’s representation area  Phantom limb Amputee patients commonly continue to experience sensation in limbs that have been surgically removed These sensations may be painless feelings of tingling, temperature, or itching, in which case the term “phantom sensation” is used If patients experience squeezing, throbbing, or burning pain coming from their amputated limb, and this is called “phantom pain” This pain is not mainly coming from the remaining stump of the amputated limb It is caused by continuous signals from the nerve endings of the missed part, in addition to changes happening in the cortex after the actual body part is no longer present  How can Phantom limb be treated ? The brain is ‘tricked’ by ‘re-incorporating’ the Phantom Limb with the mirror box leading to rapid loss of phantom limb pain The box is divided in the center with a mirror so that, when looked at from an angle, the patient has a view that projects a reflection of the real arm into the visual space occupied by the phantom arm In this way, the patient is able to view his phantom limb as normally functioning and pain-free The brain thus recreates the body schema (rapid perceptual reorganization) Ramachandran & Altschuler, 2009 The pain experience can be increased 1. Nocebo….suggestion The nocebo effect is when a negative expectation of a phenomenon causes it to have a more negative effect than it otherwise would 2. Stress induced hyperalgesia e.g. dentist 3. Presence of Inflammation 4. Presence of a neuropathic pain…damage to the nervous system  Inflammatory pain Pain arising as a consequence of inflammation to the body usually follows injury It is well controlled initially by drugs such as ibuprofen (non- steroidal anti-inflammatory drugs: NSAIDS) and newer drugs that block nerve growth factor (NGF) driven sensitization  Neuropathic pain Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system It is poorly controlled by drugs but some success with tricyclic antidepressants e.g. Trigeminal neuralgia Trigeminal neuralgia is a condition characterized by episodes of unilateral intense facial pain that lasts from a few seconds to several minutes or hours The pain occurs in areas of the face where the trigeminal nerve supplies normal sensation: cheek, jaw, teeth, gums and lips, and sometimes the eye or forehead  Neuropathic pain (cont.) Trigeminal neuralgia causes sudden, sharp and very severe pain, usually only on one side of the face The pain is described as feeling like stabbing electric shocks, burning, crushing, exploding or shooting pain Patients describe areas on the face as being so sensitive that lightly touching the face or even air currents can trigger an episode of pain However, in many patients, the pain is generated spontaneously without any apparent stimulation Rational approaches to the control of pain understanding the neurobiology How are pain-related networks organized and controlled? Pain pathway: 1. Receptors 2. Peripheral sensory nerves (unmyelinated C fibers or myelinated A delta fibers) 3. 1st order neuron : ipsilateral (same side)dorsal root ganglia (DRG) 4. 2nd order neuron: ipsilateral dorsal horn of spinal cord 5. 3rd order neuron: contralateral Thalamus 6. Fibers ascends to the contralateral cortex Pain pathway Pain pathway Receptors: free sensory nerve endings Pain Pathway (cont.) 1st order neuron 1st order neuron: Dorsal root ganglia (DRG) Dorsal root ganglia has a peripheral branch which form Central branch DRG the sensory nerve fiber and a central branch heading to the posterior horn to synapse with the 2nd order neuron Peripheral branch (sensory nerve) Observe the destination of the sensory pain fibers Pain Pathway (cont.): How does the pain information reaches the brain? 2nd order neuron: Dorsal horn neuron 3rd order neuron : thalamic nucleus From the ipsilateral dorsal horn of Axons of projection neurons in laminae I the spinal cord axons cross to the and V carried in the lateral contralateral side forming two spinothalamic tract end in 3rd order major ascending pain pathways : neurons of the thalamus which relay the pain information to the sensory cortex and cingulate gyrus – The lamina I pathway During their pathway, axons from the – The lamina V pathway dorsal horn target several brain regions: Forming the paleospinothalamic rostromedial-ventral medulla (RVM) and and neospinothalamic tracts periaqueductal grey area (PAG) in collectively called the lateral spino- midbrain (slide 17) thalamic tract Behavioral correlates of primary and central sensitization Allodynia: touch becomes painful Hyperalgesia: painful stimulation becomes more painful Primary and central sensitization Primary sensitization Central sensitization Dorsal horn neuron Mainly C fibers Mainly triggered by a Mainly triggered by a mechanical stimulus thermal stimulus C fibers DRG ❑ Maintained central sensitization is the hallmark of chronic pain states O’Neil et al, EJP 2007  Maintained central sensitization is the hallmark of chronic pain states (cont.) Patients with lower back pain experienced saline evoked muscle pain to be significantly more intense, more widespread and of longer duration than controls Hypertonic saline injected into the anterior tibialis muscle often evoke referred pain to the ankle in healthy controls but in chronic musculoskeletal pain, proximal spread of pain is often seen A wide spread and more intense effects are seen in the infraspinatus muscle response to hypertonic saline injection in chronic pain states Central sensitization is suspected  But how does the brain talk to the dorsal horn ? Is there a descending pathway? Yes!! Through the Rostromedial ventral medulla (RVM) Descending pathways from the rostromedial-ventral medulla (RVM) which is a group of neurons located close to the midline on the floor of the medulla oblongata to dorsal horn neuron can both inhibit or facilitate the pain experience depending on the released neurotransmitter (noradrenalin, GABA, seretonin, glutamate..) Descending pathways 1.Descending pain inhibitory pathways from: anterior cingulate cortex (ACC) to PAG (encephalin) to RVM (off neurons and raphe magnus nucleus) to dorsal horn neurons Raphe magnus nucleus have serotonergic axons (releasing serotonin) projecting to dorsal horn for pain Opiate modulation analgesia 2. Descending pain facilitatory pathway from RVM (ON neurons) and their ablation prevents maintenance of chronic pain What about opiates ? So should opiates be given to chronic pain patients ? Yes Is there a risk of addiction ? Very little This is mainly due to the diminished ability of opiates to produce positive reinforcement by the presence of chronic pain Also the efficacy of opioids in stimulating the dopaminergic system (reward system) is suppressed in neuropathic pain Opioids are substances that act on opioid receptors to produce morphine-like effects Opioids include opiates, an older term that refers to such drugs derived from opium, including morphine itself For this and other reasons it is very unlikely that opiates given for non-terminal chronic pain conditions will result in addiction, …unless there is a history of drug taking Addiction is a condition defined by relapse, compulsive drug taking and the emergence of a negative emotional state -‘withdrawal’ References Fields, H. L. (2009). The Psychology of Pain. Sci Am Mind, 42-49 Fields, H. (2004). State-dependent opioid control of pain. Nature Reviews Neuroscience, 5(7), 565-575 Eippert et al (2009). Activation of the Opioidergic Descending Pain Control System Underlies Placebo Analgesia. Neuron 63(4):533-543 Ramachandran, V. S., & Altschuler, E. L. (2009). The use of visual feedback, in particular mirror visual feedback, in restoring brain function. Brain : a Journal of Neurology, 132(7), 1693-1710  References Marinus et al., 2011; Clinical features and pathophysiology of complex regional pain syndrome Lancet Neurology Vol.10: 637–48 O’Neil et al, 2007 Generalized deep-tissue hyperalgesia in patients with chronic low-back pain. European journal of pain vol. 11: 415- 420 Todd, A. J. (2010). Neuronal circuitry for pain processing in the dorsal horn. Nature Reviews Neuroscience, 11(12), 823-836 Staud R. (2013). The important role of CNS facilitation and inhibition for chronic pain. Int J Clin Rheumtol. Vol. 8: 6639-646 References Ewan, E. E., & Martin, T. J. (2011). Opioid Facilitation of Rewarding Electrical Brain Stimulation Is Suppressed in Rats with Neuropathic Pain. Anesthesiology, 114(3), 624- 632 Navratilova, E., & Porreca, F. (2014). Reward and motivation in pain and pain relief. Nature Publishing Group, 17(10), 1304-1312 THANK YOU