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74 Cards in this Set
- Front
- Back
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Primary afferent sensory classes
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A Alpha – largest diameter, heavily myelinated, muscle spindles
A Beta – large diameter, heavily myelinated, low threshold mechanical muscle spindles (most innocuous tactile info) A Delta – smaller diameter, lightly myelinated, innocuous cool, noxious heat, noxious mechanical C – smallest diameter, unmyelinated, innocuous warm, noxious cold, noxious mechanical |
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Mechanoreceptors
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A-beta caliber fibers
Heavily myelinated Rapidly conducting Specialized end-organs serve as transducers |
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Response properties of low threshold mechanoreceptive primary afferent neurons
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Slowly adapting fires as long as the skin is deformed or the object is in contact with the body.
Rapidly adapting fire only on stimulus onset |
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LOW THRESHOLD MECHANORECEPTORS OF THE GLABROUS SKIN
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Meissner’s Corpuscle - rapidly adapting, coding of stimulus timing, localized sense of flutter, superficial
Pacinian Corpuscle - rapidly adapting, coding of stimulus timing, diffuse perception of vibration, deep Merkel’s Disk - slowly adapting, coding of spatial features of a stimulus (location on body), superficial Ruffini’s Corpuscle - slowly adapting, activated by skin stretch, deep |
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LOW THRESHOLD MECHANORECEPTORS OF THE HAIRY SKIN
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Hair Receptors, deep
No Meissner’s Corpuscles Pacinian Corpuscle Merkel’s Disk Ruffini’s Corpuscle |
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Proprioception overview
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Detect passive changes in joint angle as small as 0.2°
Joint position encoded by three mechanisms 1. Joint receptors A. Free Nerve Endings B. Paciniform Corpuscles C. Ruffini’s Corpuscles 2. Muscle spindles 3. Cutaneous receptors |
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ROLES OF JOINT, MUSCLE, AND CUTANEOUS RECEPTORS IN PROPRIOCEPTION
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Hip Replacement:
-Total removal of the joint produces no loss of perception of static joint position Anesthetization of Skin and Joint: -Slight impairment of movement detection Activation of Muscle Spindles by Vibration: -Evokes the illusion of Movement Conclusion: -Joint, muscle, and cutaneous input all contribute to proprioception |
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INNOCUOUS WARMTH
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Warmth responsive afferents have no specialized endings and are described as free nerve endings
Specialized transient receptor potential ion channels (TRPV3, TRPV4) contribute to the transduction of innocuous warmth Warmth afferents are small diameter, slowly conducting unmyelinated C afferents Warmth afferents increase discharge frequencies as skin temperature is raised within the innocuous range (35°C to 45°C) |
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INNOCUOUS COOL
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Cool responsive afferents have no specialized endings and are described as free nerve endings
Specialized transient receptor potential ion channels (TRPM8, activated by menthol) contribute to the transduction of innocuous cool Cool afferents are small diameter, slowly conducting, lightly myelinated A-delta afferents Cool afferents increase discharge frequencies as skin temperature is lowered (35°C to 0°C) |
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C POLYMODAL NOCICEPTORS
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No specialized end-organs and are described as free nerve endings
Unmyelinated, slowly conducting C caliber afferents C-polymodal nociceptors have transient receptor potential ion channels (TRPV1, TRPV2) that are activated by noxious heat, acid, and capsaicin (active ingredient of chile peppers) Also transduce noxious mechanical information (possibly with a specialized ion channel) Associated with a summating, late onset burning pain |
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A-DELTA NOCICEPTORS
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No specialized end organs, but used specialized ion channels to transduce information
Lightly myelinated, slow to moderate conduction velocity One population responds exclusively to noxious mechanical information, another to both noxious heat and mechanical Associated with sharp, well-localized pricking pain |
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SELECTIVE ACTIVATION AND DEACTIVATION OF PRIMARY AFFERENTS
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Local anesthetics:
-Small diameters before large diameters Compression/ischemia: -Large diameters before small diameters Electrical stimulation: -Large diameters before small diameters |
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First and second pain
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Myelinated A-deltas
-first pain Unmyelinated C -second pain |
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PERIPHERAL TARGETS FOR ANALGESIA AND ANESTHESIA
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Prostaglandin synthesis - Cytooxygenase inhibitors such as aspirin and ibuprofen minimize inflammatory pain
Nerve block - direct application of a local anesthetic such as lidocaine or bupivicaine to a nerve blocks sodium channels and information transmission Sympathetic block - local anesthetic blocks of the sympathetic ganglia reduce sympathetically maintained pain Dorsal Rhizotomy - surgical treatment of the dorsal root (Gamma Knife) can be useful in the treatment of some forms of trigeminal neuralgia. |
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EFFECTS OF SPINAL LESIONS ON TOUCH AND PROPRIOCEPTION
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Dorsal Column Lesions
-Loss of ability to process the direction of movement of a stimulus over the skin, although the ability to detect movement is preserved. -Loss of ability to discriminate between depths of skin indentation -Loss of rapid and accurate regulation of the force of distal movements Anterolateral Quadrant Lesions -Mild elevation of tactile thresholds -Major, but transient loss of pain and temperature |
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EFFECTS OF LESIONS OF SI ON TOUCH
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The ability to perceive light touch may be impaired in body regions contralateral to the affected hemisphere
Proprioception is severely impaired contralateral to the affected hemisphere Discriminative touch is severely impaired contralateral to the affected hemisphere The sensory loss is somatotopically appropriate |
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DEFINITION OF PAIN
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Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage
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Pain thresholds
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The range of stimulus magnitudes over which the
probability of perceiving pain increases from 0 to 1 |
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NOCICEPTIVE NEURONS OF THE DORSAL HORN OF THE SPINAL CORD
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Wide dynamic range neuron
-brush, press, pinch, squeeze -responds to innocuous or noxious stimulus -lamina 5 -larger receptive field Nociceptive specific neuron -responds to high intensity noxious information -lamina 1 -smaller receptive field |
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Referral of pain
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Heart attack
-L face, arm, and hand -primary afferents from these cutaneous regions synapse on same neurons that also receive info from heart |
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EXCITATORY SPINAL NEUROCHEMISTRY
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Small diameter primary afferents release both glutamate and substance P
Both neurotransmitters evoke excitatory activity in 2nd order nociceptive neurons Both neurotransmitters may produce long-duration increases in excitability which correlate with exacerbated pain Glutamate excitation via the NMDA (n-methyl-d-aspartate) receptor can be blocked with antagonists such as ketamine, PCP, and dextromethorphan |
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INHIBITORY SPINAL NEUROCHEMISTRY
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Neurons within the dorsal horn are rich in both opioid receptors and endogenous opioids such as enkephalin
GABA and glycine also play substantial modulatory roles Activation of alpha-2 adrenergic receptors can also inhibit the transmission of pain |
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SPINAL TARGETS FOR ANALGESIA AND ANESTHESIA
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Opioid receptors - acute spinal injections of fentanyl, chronic opioid infusions with an intrathecal pump
Sodium channels - acute spinal injections of bupivicaine |
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Thalamus and pain
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Nuclei receiving spinal nociceptive input:
-Ventro-posteriolateral nucleus (VPL, VPM- trigeminal) -Medial dorsal nucleus (MD) -Intralaminar nuclei Role in Pain: -Relay and modulation of ascending nociceptive information Effects of Lesions on Pain: -VPL lesions produce contralateral increases in pain thresholds -Development of chronic pain (Central Pain) Targets for Analgesia: -Opioid receptors -Deep brain stimulation |
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Primary somatosensory cortex and pain: input, role, effect of lesion, analgesia target
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Thalamic Nociceptive Input:
-VPL (body) -VPM (face) Role in Pain: -Processing of sensory dimensions of pain such as location and intensity Effects of Lesions on Pain: -Increased thresholds -Development of chronic pain (Central Pain) Targets for Analgesia: -Opioid receptors (sparse)? |
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SECONDARY SOMATOSENSORY CORTEX and pain: input, role, lesion, analgesia
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Thalamic Nociceptive Input:
-Ventroposterior Inferior (VPI) -VPL Role in Pain: -Processing sensory features of pain Effects of Lesions on Pain: -Pronounced increase in pain thresholds Targets for Analgesia: -Opioid receptors |
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Anterior cingulate cortex and pain: input, role, lesion, analgesia
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Thalamic Nociceptive Input:
-Mediodorsal nucleus -Intralaminar nuclei Role in Pain: -Attention -Expectation -Negative affect of pain Effects of Lesions on Pain: -Reduction in pain-related affective responses in chronic, but not acute pain Targets for Analgesia: -Opioid receptors -Psychological manipulations -Placebos -Hypnosis -Expectations |
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Insular cortex and pain: input, role, lesion, analgesia
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Thalamic Nociceptive Input:
-Medial Dorsal Nucleus -Intralaminar Nuclei -Ventroposterior Inferior Role in pain: -Expectations -Evaluation Effects of Lesions on Pain: -Disruption of understanding the meaning and significance of pain Role in Analgesia: -Activated by opioids |
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Prefrontal cortex and pain: input, role, lesion, analgesia
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Nociceptive Input:
-No direct spino-thalamic input Role in Pain: -Attention -Affect -Working Memory -Evaluation -Expectation Effects of Lesions on Pain: -Disruption of understanding the meaning of pain -Disrupted pain-related affect Role in Analgesia: -Activated by opioids and by placebos |
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Gate control theory
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Large diameter neuron briefly excites T, but at same time turns on inhibition so excitation is limited
Small diameter neuron excites T but turns off inhibition -Drives neuron much more Central control -comes from brain and regulates, turning things off Think of slamming hand in car door (small diameter, pain), and then shaking (large diameter, reduces pain) |
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PAIN INHIBITION BY INPUT OF LARGE DIAMETER PRIMARY AFFERENTS
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Dorsal Column Stimulation
Trans-cutaneous electrical nerve stimulation Acupuncture? Physical Therapy |
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Descending control of pain
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During extreme situations (ie combat, religious rites), significant injuries can be sustained with minimal reports of pain
Such situations may activate the midbrain periaqueductal grey matter (PAG) through endogenous opioids -Neurons from the PAG project to the nucleus raphe magnus (NRM) -Neurons from the NRM project to the dorsal horn and inhibit nociceptive activity Locus ceruleus -descends to spinal cord |
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Impact of pain
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Over 50 million Americans suffer from chronic pain each year due to injuries or surgery
Only 1 in 4 of those with pain receive proper treatment 1 in 3 American adults loses more than 20 hours of sleep each month due to pain Pain costs an estimated $100 billion each year Lost workdays due to pain add up to over 50 million per year |
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Qualitative pain measures
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Pain descriptors (nominal scale)
Stabbing, electric shock-like -May respond to anticonvulsant therapy -Trigeminal Neuralgia Burning, aching, throbbing -May respond to opioid therapy -Complex Regional Pain Syndrome (CRPS) |
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Allodynia and hyperalgesia
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SENSORY CHANGES DURING CHRONIC PAIN
Allodynia -Pain evoked by a stimulus which would normally be innocuous Hyperalgesia -Excessive pain from a normally painful stimulus |
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Neuropathic pain
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Pain initiated or caused by a primary lesion or dysfunction in the nervous system
Examples -Post-herpetic neuralgia (PHN) -Complex regional pain syndrome (CRPS) |
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Post herpetic neuralgia
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A chronic pain syndrome which follows a herpes zoster (shingles) eruption
Almost always limited to a single, unilateral dermatome that was the site of the shingles eruption Resting pain Mechanical allodynia (~78%) Thermal allodynia and hyperalgesia (~40%) Sensory loss including anesthesia |
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COMPLEX REGIONAL PAIN SYNDROME (CRPS)
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A chronic pain syndrome characterized by regional pain and sensory changes following a noxious event
Includes the disorders formally known as reflex sympathetic dystrophy and causalgia Generally results from an injury to a peripheral nerve, although in many instances the nerve injury may be undetectable Sprains, fractures, and surgeries are the most frequent initiating injuries Symptoms: -Constant burning pain -Mechanical allodynia and hyperalgesia -Thermal allodynia and hyperalgesia -Edema, sudomotor changes, atrophy of the nails, loss of joint mobility -Not limited to the distribution of a single nerve -Bilateral symptoms in 16% of patients with unilateral injury -May have sympathetic involvement |
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PERIPHERAL SENSITIZATION
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Injured nerve sprouts during regeneration
Spontaneous discharges of axons arise from the sprout Axons demonstrate increased sensitivity to mechanical stimuli Axons abnormally express adrenergic receptors |
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CENTRAL SENSITIZATION
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Wide dynamic range neurons receive input from both A-beta, A-delta, and C-fibers
Barrage of glutamate from C-fibers produces sensitization via NMDA and kainate/AMPA receptors Sensitized WDR neurons respond more robustly to all of their inputs |
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DEATH OF INHIBITORY NEURONS
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Animal models of neuropathic pain exhibit dark neurons in the dorsal horn of the spinal cord
These dark neurons are thought to be signs of dying neurons These dying cells are thought to be predominantly GABA-ergic inhibitory interneurons Formation of dark neurons in models of neuropathic pain is inhibited by NMDA antagonists |
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NON-OPIOID ANALGESICS
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Non-steroidal anti-inflammatory drugs (NSAIDs)
-Aspirin, Ibuprofen, Celecoxib -Inhibit cyclooxygenase and block the production of prostaglandins -Current evidence suggests both peripheral and central sites of action |
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ADJUVANT ANALGESICS
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A pharmacologically diverse group of drugs which have primary indication other than pain, but which may be analgesic in selected circumstances
Multipurpose analgesics -Tricyclic antidepressants, alpha-2 agonists, corticosteroids Selective activity in neuropathic pain -Local anesthetics, anticonvulsants, GABA agonists, sympatholytics |
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Opioid analgesics
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A family of drugs binding to mu, delta, and/or kappa opioid receptors
Mu agonists are highly potent analgesics (ie morphine, fentanyl) -Tolerance, sedation, constipation, respiratory suppression are major side effects -Minimal abuse liability in patients with no Hx of chemical dependency -Can be administered either centrally (intrathecal pump) or systemically (oral, intramuscular, or transcutaneous) Kappa agonists (ie pentazocine) are weaker analgesics and associated with dysphoric side-effects |
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TREATMENT OF POST-HERPETIC NEURALGIA
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Tricyclic antidepressants (ie amitriptyline)
-Combined blockade of norepinephrine and serotonin reuptake is better than blockade of serotonin reuptake alone Opioids Sodium channel blockers (local anesthetics) -Effective either topically or systemically at sub-anesthetic doses |
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TREATMENT OF COMPLEX REGIONAL PAIN SYNDROME
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The average patient is prescribed 5.2 different kinds of treatments
Physical therapy Nerve blocks Tricyclic antidepressants Opioids Anticonvulsants Psychological treatment |
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Pharmacological classes of opiates
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Agonists
-morphine Antagonists -naloxone Agonist-antagonist (partial agonists) -nalorphine |
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Partial agonists are partial antagonists
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Morphine: full agonist; potent analgesic
Nalorphine: partial agonist. Its effects depend on the individual drug state: -In opiate-free individuals: nalorphine is as potent as morphine as an analgesic. -In opiate-dependent individuals (i.e., morphine-tolerant), nalorphine produces withdrawal |
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Characteristics of morphine analgesia
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1. Profound (effective for severe pain)
2. Selective -receptors 3. Reversed by naloxone 4. More effective against dull pain 5. Does not (usually) alter pain perception, but does reduce affective reaction -Can still feel pain but just don't care 6. Blocks spinal reflex |
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Mode of action of opiates
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1. Neurophysiology: opiates reduce neuronal firing rates:
- region-specific - blocked by naloxone 2. Opiate receptors on neuronal membranes: - agonists vs. antagonists - stereospecificity - specific localization in brain and spinal cord - multiple opiate receptors: 1) mu 2) delta 3) kappa |
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Mu receptors: prototype agonist, antagonist, ligand, distribution
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Prototype agonist: morphine
Prototype antagonist: naloxone Endogenous ligand: beta-endorphin? Distribution: analgesia areas (thalamus, PAG, dorsal horn), accumbens, brainstem (respiration), basal ganglia. |
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Delta receptors: endogenous ligand, distribution
Kappa receptors: agonist example, endogenous ligand, distribution |
Delta receptors:
Endogenous ligand: enkephalins Distribution: amygdala, accumbens, dorsal horn, basal ganglia. Not in brainstem. Kappa receptors: Agonist example: pentazocine (Talwin®) (also a partial mu agonist) Endogenous ligand: dynorphin Distribution: analgesia areas (thalamus, PAG), basal ganglia. Not in brainstem. |
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Opioid peptides (endorphins): overview
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In brain, three opioid peptides represent different neurotransmitter systems (different distribution, different pharmacology, different precursors):
1. Enkephalins: pentapeptides -Met-enkephalin -Leu-enkephalin 2. beta-Endorphin: 31 aa peptide - Contains met-enkephalin - Released from pituitary during stress 3. Dynorphin: 17 aa peptide - Contains leu-enkephalin |
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Properties of enkephalins
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1. Bind with high affinity to opiate receptors (delta).
2. Regional distribution parallels (approx.) opiate receptors 3. Analgesia is produced by enkephalins (icv): -- reversed by naloxone -- much less potent than morphine 4. Unstable 5. Addictive potential equal to morphine 6. Endogenous analgesia? |
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How enkephalin works
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Firing of primary sensory neuron releases substance P.
-substance P crosses synapse and binds to receptors -excitatory Interneurons -enkephalin (inhibitory) is released and binds to presynaptic junction of primary sensory neuron -inhibits release of substance P Morphine works in a similar way but has a much larger effect (more stable) |
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Pharmacological classes of opiates
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Agonists
-morphine Antagonists -naloxone Agonist-antagonist (partial agonists) -nalorphine |
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Partial agonists are partial antagonists
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Morphine: full agonist; potent analgesic
Nalorphine: partial agonist. Its effects depend on the individual drug state: -In opiate-free individuals: nalorphine is as potent as morphine as an analgesic. -In opiate-dependent individuals (i.e., morphine-tolerant), nalorphine produces withdrawal |
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Characteristics of morphine analgesia
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1. Profound (effective for severe pain)
2. Selective -receptors 3. Reversed by naloxone 4. More effective against dull pain 5. Does not (usually) alter pain perception, but does reduce affective reaction -Can still feel pain but just don't care 6. Blocks spinal reflex |
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Mode of action of opiates
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1. Neurophysiology: opiates reduce neuronal firing rates:
- region-specific - blocked by naloxone 2. Opiate receptors on neuronal membranes: - agonists vs. antagonists - stereospecificity - specific localization in brain and spinal cord - multiple opiate receptors: 1) mu 2) delta 3) kappa |
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Mu receptors: prototype agonist, antagonist, ligand, distribution
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Prototype agonist: morphine
Prototype antagonist: naloxone Endogenous ligand: beta-endorphin? Distribution: analgesia areas (thalamus, PAG, dorsal horn), accumbens, brainstem (respiration), basal ganglia. |
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Delta receptors: endogenous ligand, distribution
Kappa receptors: agonist example, endogenous ligand, distribution |
Delta receptors:
Endogenous ligand: enkephalins Distribution: amygdala, accumbens, dorsal horn, basal ganglia. Not in brainstem. Kappa receptors: Agonist example: pentazocine (Talwin®) (also a partial mu agonist) Endogenous ligand: dynorphin Distribution: analgesia areas (thalamus, PAG), basal ganglia. Not in brainstem. |
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Opioid peptides (endorphins): overview
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In brain, three opioid peptides represent different neurotransmitter systems (different distribution, different pharmacology, different precursors):
1. Enkephalins: pentapeptides -Met-enkephalin -Leu-enkephalin 2. beta-Endorphin: 31 aa peptide - Contains met-enkephalin - Released from pituitary during stress 3. Dynorphin: 17 aa peptide - Contains leu-enkephalin |
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Properties of enkephalins
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1. Bind with high affinity to opiate receptors (delta).
2. Regional distribution parallels (approx.) opiate receptors 3. Analgesia is produced by enkephalins (icv): -- reversed by naloxone -- much less potent than morphine 4. Unstable 5. Addictive potential equal to morphine 6. Endogenous analgesia? |
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How enkephalin works
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Firing of primary sensory neuron releases substance P.
-substance P crosses synapse and binds to receptors -excitatory Interneurons -enkephalin (inhibitory) is released and binds to presynaptic junction of primary sensory neuron -inhibits release of substance P Morphine works in a similar way but has a much larger effect (more stable) |
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Pharmacological actions of opiates:factors affecting potency
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The paradox of codeine and morphine:
Codeine is 10 times less potent than morphine as an analgesic, yet 5000 times less potent than morphine in binding to mu receptors. How can codeine be an effective analgesic? 1. Receptor affinity -codeine doesn't bind as well 2. Route of administration -codeine better orally 3. Permeability through blood-brain barrier -codeine with methyl group penetrates much better -heroin even better 4. Metabolism: - liver inactivation - brain: demethylases convert codeine to morphine (technically a "prodrug") |
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Non-analgesic actions of morphine
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A. Central effects: mu receptors in brainstem
1. Respiratory depression 2. Pupil: miosis 3. Nausea 4. Cough: anti-tussive 5. Mood: sedation, euphoria 6. Hormonal effects: e.g., increase ADH B. Peripheral effects: inhibit smooth muscle contraction 1. Gastrointestinal tract: anti-diarrheal 2. Uterus 3. Bile tract 4. Orthostatic hypotension |
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Opiate agonists
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Pure mu agonists
Morphine -strong potency Heroin -strong potency -not used as analgesic because its a schedule 1 drug Codeine -weak potency -good oral Oxycodone (percodan) -moderate potency Meperidine (demerol) -moderate potency -less smooth muscle effects Diphenoxylate (lomotil) -very weak potency -not absorbed in gi tract -good antidiarrheal Methadone (dolophine) -strong potency -very orally available Propoxyphene (darvon) -very weak potency -not very effective Etorphine (immobilon) -very strong -elephant tranquilizer |
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Opiate antagonist and agonist-antagonist
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Naloxone (narcan)
-antagonist -iv Naltrexone (trexan) -antagonist -oral -used to treat addiction (after someone has gone through withdrawal) Nalorphine (naline) -agonist-antagonist Pentazocine (talwin) -agonist-antagonist -dysphoric side effects (nightmares, hallucinations) |
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Opiate addiction properties
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tolerance, physical dependence, and psychological dependence
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Tolerance and morphine
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Morphine tolerance:
Normal anal. dose: 10 mg Normal lethal dose: 50 mg Normal addict dose: >100 mg Highest dose on record: 5 grams! |
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Opioid tolerance: cross tolerance, no tolerance, mechanism
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Cross - tolerance
-- tolerance within classes of opioid agonists, not other CNS depressants -- basis for methadone maintenance No tolerance to: -- miosis -- constipation Mechanism: pharmacodynamic (not metabolic), involving mixture of receptor desensitization and signal transduction |
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Physical dependence (withdrawal)
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Symptoms: reverse effects of opiate agonists
-- almost never fatal -- treated pharmacologically (e.g., clonidine) Methods: -- abstinence -- precipitated withdrawal |
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Psychological dependence
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Most important component of addiction; distinguished from physical dependence
Compulsive drug - seeking behavior Reinforcement mechanisms |
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Treatment of opiate addiction
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Abrupt abstinence (medieval)
Graduated abstinence - drug - free - antagonist treatment (Naltrexone) Methadone maintenance -oral, better public health -slower absorption, less mood effects Buprenorphine treatment -partial mu agonist -doesn't have nasty dysphoric effects -very low efficacy, just enough to reduce craving |
