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PAIN MODELS RATIONALE, TESTING, AND INTERPRETATION NEUROPATHIC PAIN MODELS 1 Martin Oudega, Ph.D. Departments of Physical Medicine & Rehabilitation, Neurobiology, and Bioengineering Centers for the Neural Basis of Cognition and Neuroscience University of Pittsburgh School of Medicine Pittsburgh, PA 15213, U.S.A. OUTLINE GENERAL INTRODUCTION: - Neuropathic pain. - SCI, TBI, stroke. CLINICAL PRESENTATION: - Manifestation. - Management. MODELS: - Animals. - Allodynia, hyperalgesia. - Analyses. SPONTANEOUS (TONIC) PAIN: - Assessment. - Analyses. OUTLINE GENERAL INTRODUCTION: - Neuropathic pain. - SCI, TBI, stroke. CLINICAL PRESENTATION: - Manifestation. - Management. MODELS: - Animals. - Allodynia, hyperalgesia. - Analyses. SPONTANEOUS (TONIC) PAIN: - Assessment. - Analyses. NEUROPATHIC PAIN Definition: pain caused by damage or disease affecting any part of the nervous system involved in bodily feelings (somatosensory system). Pain syndromes: 1. spontaneous pain – not dependent on peripheral stimuli “persistent numbness, burning, cutting, piercing, electric-like” 2. peripherally evoked pain: response to (non-)noxious stimuli PAIN - ANATOMY somatosensory system: peripheral sensors (skin, epithelia, muscles, bones, joints, organs, cardiovascular system) to central processing areas. Pain: nociception through nociceptors. Information pathway: nociceptor (transduction) - sensory nerve (transmission) - spinal cord (modulation) - brain (perception). Spinothalamic tract (STT) STT location in spinal cord PAIN - ANATOMY Components of the pain pathway: Neurons: primary (DRG/trigeminal ganglia: periphery (receptor)-spinal cord) secondary (spinal cord/brainstem-thalamus) tertiary (thalamus (ventral posterior nucleus, VPN)-cortex) Axons: C fiber: thin, slow (unmyelinated) axon (Lamina II) (less intense) A fiber: fast, myelinated (sharp) C fibers in STT: synapse in thalamus information processing centers: primary somatosensory area in postcentral gyrus of parietal lobe of cerebral cortex. ‘locate’ pain stimulus (homunculus). Not only neurons involved, also glia, immune cells PAIN - MODULATION Modulation happens at different levels. Periaquaductal grey matter plays important role Descending inhibition to modulate pain sensation through hypothalamus-mediated release of hormones. Opioid receptors (- analgesic effects of opioids). NEUROPATHIC PAIN Origin: peripheral nervous system (peripheral neuropathic pain) central nervous system (central neuropathic pain) central and peripheral nervous system (mixed neuropathic pain) NEUROPATHIC PAIN Origin: peripheral nervous system (peripheral neuropathic pain) central nervous system (central neuropathic pain) central and peripheral nervous system (mixed neuropathic pain) CENTRAL NEUROPATHIC PAIN (CNP) Origin: central nervous system: brain – spinal cord Neuropathic pain: was defined as pain caused by damage or disease affecting any part of the nervous system involved in bodily feelings (the somatosensory system). Injury or disease: spinal cord injury, traumatic brain injury, stroke, multiple sclerosis, others NEUROPATHIC PAIN SCI, TBI, Stroke Alcoholism Amputation Back, leg, and hip problems Chemotherapy Diabetes Facial nerve problems HIV infection or AIDS Multiple sclerosis Spine surgery OUTLINE GENERAL INTRODUCTION: - Neuropathic pain. - SCI, TBI, stroke. CLINICAL PRESENTATION: - Manifestation. - Management. MODELS: - Animals. - Allodynia, hyperalgesia. - Analyses. SPONTANEOUS (TONIC) PAIN: - Assessment. - Analyses. SPINAL CORD INJURY etiology Updated: June 2009 National SCI Statistical Center Birmingham, Alabama Other Sports 8% Violence Traffic accidents 9% 42% 15% 27% Falls Incidence: Over 12,000 spinal cord injuries in U.S.A. every year Prevalence: 229,000-306,000 persons with spinal cord injury Gender: 81% of all spinal cord injuries occur in men Age: Between 16-20 (55%). Average age = 40. Neurologic level: 51% tetraplegic (cervical injury; 30%, incomplete) Over 75% of SCI are contusive injuries. SPINAL CORD INJURY CONTUSION C2 C5 C7 T2 Uninjured Over 75% of SCI is a contusive injury Contusion, solid, no cyst 15% Contusion, cyst 33% Maceration 29% Laceration 23% Bunge et al., 1993, Kakulas, 1999 SPINAL CORD CONTUSION Demyelination Oligodendrocyte death Cyst formation No growth substrate Glial Scar Surrounding the injury site Spinal cord contusion CELLULAR CONSEQUENCES DEMYELINATION ABORTIVE SPROUTING INFLAMMATION SCARRING GLIOSIS CELL DEATH LOSS BLOOD VESSELS HYPER EXCITABILITY CYSTS ISCHEMIA APOPTOSIS EDEMA Impaired function INITIALLY SECONDARY Cell death Axonal dieback Axonal damage Demyelination Hemorrhage Scar formation Inflammation Cyst formation FUNCTIONAL CONSEQUENCES X Sensory Information To brain Loss of motor function Loss of sensory function Loss of autonomic function injury Degenerating Distal part of damaged axon Interruption of descending (motor) and ascending (sensory) pathways Loss of bowel/bladder function Loss of sexual function Spasticity Central Neuropathic Pain Motor information to periphery X ENDOGENOUS REPARATIVE EVENTS UPREGULATION RAGs REMYELINATION AXON SPROUTING DEBRIS REMOVAL ANGIOGENESIS PLASTICITY STEM CELL BIRTH / PROLIFERATION SCHWANN CELL INVASION TROPHIC FACTORS FAILS TO RESTORE ANATOMY / FUNCTION FAILS TO ALLEVIATE NEUROPATHIC PAIN TRAUMATIC BRAIN INJURY Similar as SCI… Insult to head causing brain tissue damage. Secondary injury progressively worsens injury resulting in loss of tissue. Location of injury determines deficits. TRAUMATIC BRAIN INJURY TRAUMATIC BRAIN INJURY Symptoms short-term: Headaches, vomiting, nausea, convulsions, inability to awaken, pupil dilation, slurred speech, aphasia (difficulty in word finding), etc. Symptoms long-term: Changes in appropriate social behavior, deficits in social judgment, cognitive changes, attention problems, etc. STROKE Loss of brain function due to disturbance in blood supply to the brain Causes: ischemia (lack of blood flow) (80%). hemorrhage (20%) Epidemiology: frequent cause of death (>6 million/world) 95% in people over 45 years old. Symptoms: starts suddenly, lasts seconds/minutes. symptoms depend on area affected. additional symptoms due to compression of other areas STROKE Pathophysiology is ‘similar’ as in SCI and TBI with progressive loss of nervous tissue. OUTLINE GENERAL INTRODUCTION: - Neuropathic pain. - SCI, TBI, stroke. CLINICAL PRESENTATION: - Manifestation. - Management. MODELS: - Animals. - Allodynia, hyperalgesia. - Analyses. SPONTANEOUS (TONIC) PAIN: - Assessment. - Analyses. CNP-CLINIC After SCI/TBI/Stroke, if damage affects primary somatosensory area (postcentral gyrus of parietal lobe) or along the STT Prevalence: SCI, 60-80%; Stroke, 10% SCI most common cause for central pain. Mechanisms include central disinhibition and/or central sensitization (STT neurons have increased background activity, enlarged receptive fields, and increased responses to afferent impulses, even non-noxious). Not completely understood at this time. More later. CNP - CLINIC Manifestation: -develops within weeks/months. -described as: burning, stabbing, electric-like. Types of pain responses: allodynia: response to normally non-noxious stimulus. hyperalgesia: increased response to noxious stimulus. spontaneous (tonic) pain. OUTLINE GENERAL INTRODUCTION: - Neuropathic pain. - SCI, TBI, stroke. CLINICAL PRESENTATION: - Manifestation. - Management. MODELS: - Animals. - Allodynia, hyperalgesia. - Analyses. SPONTANEOUS (TONIC) PAIN: - Assessment. - Analyses. CNP - TREATMENT attempt to influence descending pain modulating pathways. Neurosurgical, pharmacological, behavioral strategies. Difficult…..40-60% achieve partial relief. Pain affects quality of life (depression-suicide). Anti-depressants (CNS - common mechanisms/different functions) tricyclica, anticonvulsants (gabapentin), topical lidocaine SNRIs (5Ht-Norepi reuptake inhibitors) anticonvulsants (pregabalin, gabapentin), topical lidocaine. Opioid analgesics (not first line treatment). OUTLINE GENERAL INTRODUCTION: - Neuropathic pain. - SCI, TBI, stroke. CLINICAL PRESENTATION: - Manifestation. - Management. MODELS: - Animals. - Allodynia, hyperalgesia. - Analyses. SPONTANEOUS (TONIC) PAIN: - Assessment. - Analyses. CNP MODELING Specific models to study pain mechanisms 1. Occlusion of blood vessels-ischemia – mechanical allodynia 2. Anterolateral spinal cord lesions – mechanical allodynia/overgrooming 3. Quisqualic injection – overgrooming (AMPA/kainate/metabotropic receptor agonist) SCI/TBI/Stroke models that ‘allow’ studying pain (not always) 1. 2. 3. 4. SCI contusion, clip compression – mechanical/thermal hyperalgesia, allodynia Hemisections – hyperalgesia, allodynia (depends on location) Brain contusions-TBI Artery occlusions-Stroke SPINAL CORD INJURY MODELS CONTUSION PARTIAL TRANSECTION COMPLETE TRANSECTION SPINAL CORD LACERATION MODELS Ad: interpretation clear-cut DA: technically difficult SPINAL CORD CONTUSION Compression Impact Velocity NYU Contusion Device Impact Contused cord HUMAN VS RAT SPINAL CORD CONTUSION 3 months TBI MODELING Lateral Fluid Percussion STROKE MODELING Many mechanisms that lead to (ischemic) stroke including cardiac arrest, hypoxia, blood clot embolization, but most used is MCA, middle cerebral artery occlusion MCA is one of three major paired arteries that supply blood to brain. Occlusion leads to MCA syndrome: damage to brain hemisphere paralysis of (contralateral) face/arm sensory loss (contralateral) face/arm OUTLINE GENERAL INTRODUCTION: - Neuropathic pain. - SCI, TBI, stroke. CLINICAL PRESENTATION: - Manifestation. - Management. MODELS: - Animals. - Allodynia, hyperalgesia. - Analyses. SPONTANEOUS (TONIC) PAIN: - Assessment. - Analyses. HOW DO WE ASSESS CNP AFTER SCI/TBI/STROKE Types of responses: allodynia: response to normally non-noxious stimulus. hyperalgesia: increased response to noxious stimulus. Types of assessments: allodynia: Von Frey aesthesiometer. hyperalgesia: Hargreaves method. ALLODYNIA: VON FREY AESTHESIOMETER Maximilian von Frey ALLODYNIA: VON FREY AESTHESIOMETER THERMAL HYPERALGESIA: HARGREAVES THERMAL HYPERALGESIA: HARGREAVES OUTLINE GENERAL INTRODUCTION: - Neuropathic pain. - SCI, TBI, stroke. CLINICAL PRESENTATION: - Manifestation. - Management. MODELS: - Animals. - Allodynia, hyperalgesia. - Analyses. SPONTANEOUS (TONIC) PAIN: - Assessment. - Analyses. ANALYSES TIME (seconds, Hargreaves) or PRESSURE (grams, von Frey) Allodynia and hyperalgesia can be assessed using the pressure/time it takes to cause withdrawal of paw in response to tactile/thermal stimulus. In case of CNP, the time/pressure will be shorter/smaller. An effective treatment would lengthen time/increase pressure until withdrawal. EXAMPLE BMSC PRESENCE RESULTS IN IMPROVED SENSORY FUNCTION IN THE ADULT RAT WITH A CONTUSED SPINAL CORD Thermal hyperalgesia: Hargreave’s heat source. Paw withdrawal to noxious stimulus. Thermal hyperalgesia (seconds ± SEM) 16 14 12 BMSC DMEM * 10 * 8 6 4 2 0 4 weeks 8 weeks Mechanical allodynia: Von Frey aneasthesiometer. Paw withdrawal to otherwise innocuous stimulus. Mechanical Allodynia (grams ± SEM) 160 140 BMSC DMEM 120 100 * * 80 60 40 20 0 4 weeks 8 weeks OUTLINE GENERAL INTRODUCTION: - Neuropathic pain. - SCI, TBI, stroke. CLINICAL PRESENTATION: - Manifestation. - Management. MODELS: - Animals. - Allodynia, hyperalgesia. - Analyses. SPONTANEOUS (TONIC) PAIN: - Assessment. - Analyses. SPONTANEOUS PAIN Von Frey, Hargreaves are used to assess allodynia, hyperalgesia “withdrawal responses” to evoked pain or hypersensitivity In rats, are they reflecting CNP? Is it maybe a reflex to the sensation rather than a pain-related behavior? Spontaneous pain is the single most common and debilitating complaint of people with SCI How to measure spontaneous pain in rats? CPP: conditioned place preference CPP conditioned place preference: Based on the fact that relief from pain is rewarding, analgesics that are not rewarding themselves in the absence of pain should become rewarding in the presence of pain. OUTLINE GENERAL INTRODUCTION: - Neuropathic pain. - SCI, TBI, stroke. CLINICAL PRESENTATION: - Manifestation. - Management. MODELS: - Animals. - Allodynia, hyperalgesia. - Analyses. SPONTANEOUS (TONIC) PAIN: - Assessment. - Analyses. ANALYSES TIME spend in drug-associated chamber In case of spontaneous pain, should be increased