Pharmacology Exam 4 Patho

The Brain Major Regions - Sagittal View

"Brainstem" = Midbrain + Pons + Medulla. Brainstem controls: Alertness Breathing Blood Pressure Heart Rate Other Autonomic Functions Relays information between the peripheral nerves and spinal cord to the upper parts of the brain.

Peripheral Sensitization

"Inflammatory Soup": Substance P, histamine, 5-HT, NE, prostaglandins, H+ ions. Combined effect is to lower threshold for neuronal activation and increased rate of firing (generating APs) Nociceptor sensitization. Plays a role in allodynia, hyperalgesia and in central sensitization

Anxiety Disorders Definition (DSM-5)

Anxiety disorders appear to be caused by an interaction of biopsychosocial factors, including genetic vulnerability, which interact with situations, stress, or trauma to produce clinically significant syndromes. Symptoms vary depending on the specific anxiety disorder. DSM-5 restructured the anxiety disorders into 3 groups; each disorder has its own definition and criteria: Anxiety disorders Panic disorder Generalized anxiety disorder Social anxiety disorder Agoraphobia Others Obsessive-compulsive and other related disorders Obsessive-compulsive disorder Body dysmorphic disorder Hoarding disorder Others Trauma- and stressor-related disorders Post-traumatic stress disorder Acute stress disorder Adjustment disorder Others

Exceptions to the NT receptor types

We have already noted that GABAB is a metabotropic receptor. There are other poorly-understood metabotropic receptors for amino acid NTs. Exceptions to the amine NT metabotropic receptor type include: The serotonin 5-HT3 receptor is an ionotropic receptor. 5-HT3 receptors are found in the GI tract and in the brainstem vomiting center of the medulla. 5-HT3 receptors are blocked by the antiemetic drug ondansetron (Zofran). (serotonin = 5-HT = 5-hydroxytryptamine)

Major Depressive Disorder (MDD) Definition (DSM-5)

At least 5 of the following symptoms have to have been present during the same 2-week period (and at least 1 of the symptoms must be diminished interest/pleasure or depressed mood): Depressed mood. For children and adolescents, this can also be an irritable mood Diminished interest or loss of pleasure in almost all activities (anhedonia) Significant weight change or appetite disturbance. For children, this can be failure to achieve expected weight gain. Sleep disturbance (insomnia or hypersomnia) Psychomotor agitation or retardation Fatigue or loss of energy Feelings of worthlessness Diminished ability to think or concentrate; indecisiveness Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or specific plan for committing suicide

Sources of neuronal EXCITATION

At the whole brain level: an abrupt source of sensory input - loud noise, flashing light, the startle response At the cellular level: Opening of channels permeable to sodium or calcium Activation of receptors for the excitatory neurotransmitter GLUTAMATE Other sources, including activation of nicotinic receptors by acetylcholine

1. Transduction

Process of converting painful stimuli to neuronal action potentials Nociceptors transduce noxious stimuli into action potentials and are sensitized. Chemical mediators alter the membrane potential of the nociceptor increased sensitivity (and reactivity) of nociceptor to noxious stimuli. Once released, these chemicals bind and activate specific receptors on the nociceptor, increase the excitability of the neuronal cell membrane and lead to generation of an AP. Chemical mediators released include K+, H+, serotonin, bradykinins, norepinephrine, prostaglandins, others Certain prostaglandins, including PGE2, increase nociceptor sensitivity Noxious stimuli tissue damage or potential tissue damage Mechanical - touch/pressure Thermal - heat/cold Chemical - internal or external substances

Major central cholinergic neurons

Important brain region origins and associated ACh functions: 1. Basal forebrain - learning, waking Nucleus basalis of Meynert degenerates in Alzheimer's disease 2. Basal Ganglia: Striatal interneurons - antagonizes dopamine - motor control 3. Brainstem pedunculo- pontine nucleus - REM sleep initiation

Epidemiology of Pain

An estimated 25 million Americans experience acute pain and 50 million suffer chronic pain annually. Chronic pain is the leading cause of disability in the U.S. and the most common reason patients see a primary care physician. Pain results in more than 50 million lost work days per year in the United States.

Seizure threshold

the level of stimulation (balance of excitation and inhibition) which will cause a seizure. People with epilepsy have a lower-than-normal seizure threshold Each person's threshold is influenced by genetics, age, certain drugs, comorbidities (esp. brain injury).

Synapse structure and function: neurotransmitter release and binding

1. Depolarization of the nerve terminal by arrival of the action potential opens voltage-gated calcium channels. 2. Influx of Ca2+ initiates fusion of synaptic vesicles with the cell membrane and then release of neurotransmitter (T) into the synaptic cleft via exocytosis. 3. The neurotransmitter diffuses across the cleft and binds to receptors on the postsynaptic cell membrane.

The Effect on Serotonin after Weeks of Treatment with SSRI

1. Initially after starting SSRI treatment ("Acute Treatment"), serotonin autoreceptors will inhibit the release of serotonin. 2. With chronic (weeks, at least) treatment, some autoreceptors are internalized by the midbrain raphe nuclei. This permits increased firing by the presynaptic neuron and increased release of serotonin into the synaptic cleft.

A refresher from your A&P class

1. AP propagates along presynaptic axon. 2. Voltage-gated Ca++ channels open in response to depolarization the cell membrane associated with the AP. 3. Vesicles containing neurotransmitter (NT) fuse with plasma membrane of presynaptic neuron. 4. NT diffuses into synaptic cleft and binds with receptor on postsynaptic neuron. 5. Response of postsynaptic neuron. 6. NT may bind to enzyme which degrades NT. OR 7. NT may be reuptaken into presynaptic neuron. OR 8. NT may simply diffuse away (as will the products of enzymatic degradation.)

Basic Neuronal Physiology

1. Conduction of action potential 2. Release of a neurotransmitter 3. Post-synaptic binding 4. Post-synaptic effects

A closer look at termination of transmitter action - 3 mechanisms

3a. Reuptake - most common - a form of secondary active transport that uses the movement of sodium down its concentration gradient to transport the NT against its concentration gradient back into the presynaptic terminal. There, it is either stored or broken down (storage is most common). 3b. Enzymatic breakdown (example: acetylcholine is broken down by acetylcholinesterase) 3c. Diffusion away from the synapse

Aura

: considered to be part of the seizure; at the beginning the patient may experience a particular sensory, autonomic or psychic symptom that is characteristic of seizures.

Epilepsy

A person is considered to have epilepsy if they meet ANY of the following conditions. At least two unprovoked (or reflex) seizures occurring more than 24 hours apart. One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years. Diagnosis of an epilepsy syndrome Epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but are now past the applicable age or those who have remained seizure-free for the last 10 years, with no seizure medicines for the last 5 years. Take home message: Having a single seizure does not necessarily mean a person has epilepsy.

Modulation: The Gate Control Theory

A-beta fibers normally carry information about touch, vibration or pressure, NOT pain. Inhibitory interneurons in the dorsal horn inhibit 2nd order neurons that transmit pain. C-fibers normally inhibit these interneurons, allowing the pain signal continue its journey. But A-beta fibers stimulate interneurons that in turn inhibit 2nd order pain-transmitting neurons. Hence, non-painful mechanical stimuli decreases pain transmission. Basis of therapies such as TENS units. Transduction: Noxious stimuli converted to impulses, AP generated Transmission: Movement of impulses ascending from the periphery to the spine and then to the brain Perception: Recognizing, defining and responding to the pain Modulation: Descending pathways exert inhibition or amplification on pain transmission.

Temporal and Spatial Summation

A. Spatial summation occurs when two or more presynaptic neurons release neurotransmitter onto one postsynaptic cell at the same time. The various excitatory postsynaptic potentials and inhibitory postsynaptic potentials add algebraically to determine the overall postsynaptic potential (PSP) reaching the axon hillock. B. Temporal summation occurs when one presynaptic neuron fires in rapid succession such that a previous PSP has not fully dissipated before the next PSP is added to it.

Cholinergic neurotransmission

Acetylcholine is an example of the enzymatic breakdown method of neurotransmitter termination. ACh only briefly binds with its receptors and then is enzymatically degraded to choline by acetylcholinesterase. Choline is then returned to the presynaptic nerve terminal, to be used in the re-synthesis of acetylcholine.

Acute vs. Chronic Pain

Acute Patient appears in distress Temporally related to noxious stimuli Signs (mainly SNS-mediated) - Increased or labile BP, HR, diaphoresis, mydriasis, pallor, release of epinephrine, cortisol, hyperglycemia Chronic Patient may not appear to be uncomfortable Pain extending beyond the expected time course of painful syndrome No obvious signs

Consequences of Inadequately-Treated Pain

Acute: Hemodynamic instability Post-surgical: impaired respiratory and GI function Prolonged return to function, decreased ability to participate in rehab activities Anxiety Risk of pain becoming chronic Chronic Anxiety, depression Decreased quality of life Disability, inability to work

Inflammatory Pain

Adaptive mechanism that facilitates healing of injured tissues: ensures that contact with the injured tissue is minimized until repair is complete Usually abates and resolves with healing Increases sensitivity to stimuli in affected area Example: sunburned skin Role in peripheral sensitization and central sensitization

Commonalities in signaling by dopamine, norepinephrine, serotonin

All have metabotropic receptors (5-HT3 receptor is an exception: ionotropic) All have action terminated by reuptake transporters (T) All have transmitter release modulated by autoreceptors (A) Autoreceptors are receptors for a particular NT, located on the presynaptic membrane. They provide a feedback system: when there is too much NT released in the synapse, activation of autoreceptors decreases the release of further NT when the action potential arrives at the presynaptic membrane. All have excess neurotransmitter metabolized by monoamine oxidase (M) in their presynaptic nerve terminals Dopamine and norepinephrine can also be metabolized by Catechol-O-methyl-transferase (COMT) in postsynaptic cells.

Afferent Sensory Pain Fibers

Alpha delta fibers: myelinated, 10% of fibers, mechanical and thermal stimuli, fast acting (5-10 m/s), sharp, stinging, cutting, pinching pain C fibers: unmyelinated, 90% of fibers, polymodal stimuli (mechanical, thermal, chemical), slow acting (0.6-2 m/s), dull, burning, aching pain

Definition of Pain

American Pain Society (APS): "Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage." Margo McCaffery (1968): "Pain is whatever the experiencing person says it is, existing whenever he says it does."

Amino Acid NT versus Amine NT

Amino Acid NT -signaling via ionotropic receptors -fast signaling -direct actions to cause purposeful activity and reflex activity -found in all brain regions -drugs that act on glutamate and GABA may have very widespread sensory and motor effects Amine NT: -signaline via metabotropic receptors -slow signaling -slow, modulatory, widespread activity -found in some concentrated regions, but axons spreads throughout the CNS -drugs that act on amines may affect mood, behavior, appetite, sleep, and emotions

Regions of the brain associated with depression

Amygdala Prefrontal cortex Hippocampus Thalamus

Definitions: Pain

Analgesia - reduced perception of pain stimuli Anesthesia - reduced perception of all sensation Paresthesia - abnormal sensation; not unpleasant Dysesthesia - abnormal sensation; not pleasant Allodynia -Pain response to normally non-painful stimuli Hyperalgesia - extreme pain response to painful stimuli (i.e., stimulus is expected to be painful, but response is extreme) Hyperalgesia - increased response to a stimulus that is normally painful Secondary Hyperalgesia - spread of sensitivity to noninjured areas

Basic mechanisms of seizures and epilepsy

At its most basic level, a seizure represents a disruption in the balance between neuronal excitation and inhibition Epilepsy could result from the brain having TOO MUCH excitation OR Epilepsy could result from the brain having TOO LITTLE inhibition

GABAA receptor is part of a larger GABA receptor-chloride channel complex

Binding of GABA to its receptor chloride channel opens inward flow of chloride ions hyperpolarized neuron decreased ability to fire inhibitory

Dopamine and Pleasure / Reward

The specific location of a pleasurable / reward effect of dopamine is in a forebrain region called the nucleus accumbens. Neurons from the ventral tegmental area project into the nucleus accumbens and release dopamine

Neuropharmacologic medications

Can alter axonal conduction Less common Not very selective; conducting an impulse is essentially the same in all neurons Can alter synaptic transmission Most common Can be selective; synapses have different transmitters and receptors for those transmitters. Ultimately, these medications work by influencing receptor activity on target cells.

GABAA (ionotropic) receptor function

Central pore (in ion channel) that, when open, permits chloride to flow into cell. -makes cell more negative

Mechanisms of Neuropathic Pain

Central sensitization Ectopic excitability Nerve regeneration results in sprouts and neuromas that fire spontaneously Peaks several weeks after injury Changes in expression of Na+/K+ channels Structural Reorganization Low-threshold sensory fibers terminate in areas where nociceptive neurons usually terminate. Ex: A-beta touch fibers may transmit pain impulses. Associated allodynia and hyperalgesia

Examples of Neuropathic Pain

Central: poststroke pain, pain associated with multiple sclerosis or Parkinson's disease, spinal cord injury Peripheral: post-herpetic neuralgia, diabetic neuropathy, chemotherapy-induced neuropathy, HIV sensory neuropathy, phantom limb pain

Clinical Manifestations of Seizures

Changes in motor control, sensation, behavior, consciousness, autonomic function. Combination of signs and symptoms will depend on the type of seizure. In focal seizures, specific manifestations may provide a clue to localization of an epileptogenic focus. EEG can provide further information to help localize the focus. In generalized seizures, progression of signs or some aspect of history (of head trauma, for example), can give hints regarding the brain location Detective work often needed to identify the focus of hyperexcitability Common comorbidities Psychiatric, cognitive, social Careful history is needed of the seizure events, pre- and post-ictal characteristics Historically, epilepsy led to stigmatization, marginalization, exorcism and other treatments in an effort to rid the epilepsy patient of "evil spirits". There is still much misunderstanding about seizures among the general public.

Classifying Seizures

Classified by: Type of onset (focal or generalized) Level of awareness (aware or impaired awareness) First prominent sign or symptom (motor or nonmotor) Three broad types: Focal Onset, Generalized Onset and Unkown Onset seizures. Focal onset seizures (old term: partial seizures). Activity begins in one hemisphere of the brain. May be localized or more widely distributed, but still confined to one hemisphere. May originate in cortex or subcortical structures. Most common site is temporal lobe. Can become bilateral (old term: secondarily generalized) Generalized onset seizures. Activity begins bilaterally (both hemispheres). Considered more severe than focal onset seizures. Does not have to involve the entire brain. May originate in cortex or subcortical structures. Seizures may also be classified as "Unknown onset". "Placeholder" name until more specific onset is determined. Further classification: Aware or Impaired Awareness Aware = knowledge of self and environment during the seizure. Consciousness remains intact. If awareness is impaired for any part of the seizure, then the seizure is designated "impared awareness". For focal onset, classified by: Aware (Old name: Simple partial seizure) Impaired awareness (Old name: Complex partial seizure) This classification is not used for generalized onset seizures or unknown onset seizures.. The vast majority of generalized seizures involve impaired awareness, up to and including loss of consciousness. Further classification: Motor Onset or Nonmotor Onset Refers to the first prominent sign or symptom. "Motor" involves the musculature in any form. Can be either an increase or a decrease in muscle contraction. If changes in muscular contraction are not the first prominent sign or symptom, then the seizure is classified as nonmotor. Each of these categories can be further refined/categorized.

The Cerebral Cortex

Largest part of the human brain Associated with higher brain function such as thought, language, information processing and action. Divided into four lobes: the frontal lobe, parietal lobe, occipital lobe, and temporal lobe.

What depolarizes the cell to threshold? What hyperpolarizes the cell?

Depolarization to threshold and hyperpolarization way from threshold usually involve CHEMICAL TRANSMISSION Recall the process of synaptic transmission from the Depression and Anxiety lecture The result can be excitatory or inhibitory In a healthy brain, there a balance between excitation and inhibition, so that groups of neurons do not repeatedly and synchronously "fire" inappropriately. "Synchronous" = at the same time Opposite = asynchronous

4. Modulation

Descending pathway from the brain to the dorsal horn of the spine. Complex mechanism whereby synaptic transmission of pain signals is changed; may be inhibited or amplified. Key players in inhibiting pain signals: endogenous opioids (enkephalins, endorphins and dynorphins): block release of neurotransmitters, like glutamate and Substance P serotonin (5-HT) norepinephrine (NE) GABA Notice that at this point in the descending pain pathway, serotonin and norepinephrine can reduce pain; the opposite was true in the transduction phase of the ascending pathway. "Rub it, it will feel better!": Rubbing activates non-nociceptive A-beta fibers which inhibit the transmission of nociceptive information. Known as the "gate control theory of pain".

Cognitive Behavioral Therapy (CBT)

Developed in 1960s by Dr. Aaron Beck - at Penn. Used extensively in anxiety and depression Tx. Goal is to help the patient to identify the thoughts and images that precede distressing emotions, distance themselves from the beliefs that are embedded into these thoughts and images Rationally question those beliefs Learn new behaviors and coping skills

Dravet Syndrome: An example of epilepsy caused by a gene mutation

Early-onset epilepsy syndrome characterized by refractory epilepsy and neurodevelopmental problems beginning in infancy. Mutation of the SCN1A gene (sodium voltage-gated channel alpha subunit 1), which codes for the alpha subunit of a sodium channel in the brain. About 90% of mutations arise de novo and are not inherited. Over 700 mutations have been identified. Most common type is a truncating mutation (=nonsense + certain frameshift mutation); i.e., the protein is too short. First seizure typically occurs in 1st year of life. May initially be mistaken for a febrile seizure; may be associated with an infection or recent vaccination or with no discernable trigger. Seizures increase in frequency, child may have multiple types of seizures. May have numerous seizures each day. Seizures, including the first one, may be prolonged. As seizures continue, child shows signs of neurodevelopmental delay; some children may regress. Behavioral changes may occur. Vast majority of patients have lifelong persistent and refractory seizures as well as moderate to severe cognitive impairment. Motor dysfunction is common as well Ataxia Tremor Dysarthria Spasticity and hyperreflexia Extrapyramidal signs.

Other theories of depression

Excess serum glucocorticoids (such as cortisol) appear to produce atrophy/volume reduction the hippocampus. Hippocampus contains high levels of glucocorticoid receptors, which make it more vulnerable to long-term stress than most other brain areas. Glutamate's possible role Observations that ketamine, an NMDA glutamate receptor antagonist, can bring about rapid relief of depression. Disruptions in normal gut microbiota appear to influence mood and anxiety (the brain-gut axis links emotions and GI microbiota, as well as GI function). Disruptions of melatonin regulation in response to changing light and dark (i.e., SAD) Neuroinflammation appears to play a role for some people. These individuals display elevated blood levels of IL-6, TNF-α, and other pro-inflammatory cytokines. It is unlikely that a single, unifying theory of depression pathophysiology will emerge, or is even possible.

Review of neuronal action potentials

Excitable cells have Resting membrane potential (~ -70 mV) When a neuron depolarizes to a THRESHOLD voltage, fast sodium channels open and the neuron has an ACTION POTENTIAL. Potassium plays a major role in repolarization and hyperpolarization. 1.Graded depolarization brings trigger zone of axon hillock to threshold 2. Voltage-gated Na+ channels open rapid depolarization 3. Voltage-gated Na+ channels are inactivated and voltage-gated K+ channels open repolarization 4. Slow inactivation of K+ gates undershoot (or after-hyperpolarization) 5. Ion redistribution by Na+/K+ pump restores RMP

Types of chemical transmission

Excitatory EPSPs (Excitatory Postsynaptic Potential) Makes the postsynaptic neuron > likely to generate an AP (closer to threshold; cell depolarizes) Ion channel/receptor complex selective for sodium or calcium Principal neurotransmitter - GLUTAMATE Inhibitory IPSPs (Inhibitory Postsynaptic Potential) Makes the postsynaptic neuron < likely to generate an AP (farther away from threshold; cell hyperpolarizes) Ion channel/receptor complex selective for potassium or chloride Principal neurotransmitter - GABA A single EPSP or IPSP is not sufficient to bring the cell to threshold and generate an action potential. AP requires temporal or spatial summation, or both, to occur. -temporal summation: 2 excitatory stimuli close together cause EPSPs to add together -spatial summation: 2 excitatory that happen in different places that cause EPSPs to add together -spatial summation in EPSPs and IPSPs: these can cancel each other out

Prefrontal Cortex (PFC)

Executive function of the brain: discrimination between conflicting thoughts, planning complex cognitive behaviors, working toward a goal, etc. One function of PFC is is to inhibit the activity of the amygdala, to allow focus on tasks fMRI and PET scans have shown decreased PFC activity in depressed people less inhibition of the amygdala

Depression risk factors

Genetics Family history ~ 40-50% of risk, esp. w/early age of onset. Other factors Stress Emotional trauma Comorbidities of cancer, several endocrine disorders (including hypothyroidism and diabetes), stroke,TBI, Parkinson's disease, myocardial infarction, renal failure, some acute infectious diseases (infectious mono in adolescents) Comorbid depression increases disability, morbidity, and mortality. Post-partum: 10-15% of women experience a more disabling and persistent form of depression than can be attributed to "post-partum blues". Seasonal variations in light (Seasonal Affective Disorder, SAD)

Anxiety risk factors

Genetics Panic Disorder especially, but all types of anxiety appear to have some genetic factors contributing Other factors Emotional trauma Injuries/physical trauma, illness Loss and grief Certain stimulants, including excessive caffeine, cocaine, amphetamines, MDMA ("Molly") Certain illnesses, including hyperthyroidism, pheochromocytoma Infection: Group A streptococcus infections associated with some cases of OCD in children (PANDAS)

Types of GABA receptors

GABAA: Ionotropic/Ligand-gated GABAB: Metabotropic GABAC: Ionotropic/Ligand-gated; found mainly in the retina All types of GABA receptors produce IPSPs and therefore, are inhibitory. GABA is the principal CNS inhibitory neurotransmitter.

Seizures and Epilepsy

Having a seizure is NOT the same thing as having epilepsy. Up to 10% of the population may experience a seizure in their lifetime In many cases, the cause of a single seizure is obvious: Head trauma Stroke Brain infection Tumors Eclampsia Hypoxia Hypoglycemia Hyponatremia and other electrolyte disturbances Drug or alcohol acute effect or withdrawal Childhood fever (febrile seizures) Certain "recreational" drugs, including cocaine, ecstasy/MDMA The continued occurrence of seizures, particularly with no discernible cause, is strong evidence for a new diagnosis of epilepsy U-shaped relationship between age and epilepsy incidence

Hippocampus

Hippocampus is responsible for spatial orientation and long-term memory Depressed patients may exhibit memory loss or memory recall difficulties The underlying cause is thought to be decrease in the physical volume of the hippocampus, as well as its function

Central Sensitization

Increased excitability of neurons within the CNS. increased excitability is triggered by a burst of activity in nociceptors (after injury) which alter the strength of synaptic connections between the nociceptor and the neurons of the spinal cord Ongoing nociceptive input from periphery causes gradual increase in dorsal horn (DH) neuron firing known as "wind up" Prolongation of this input results in longer-lasting DH excitability, due to changes in expression of genes via activation of transcription factors. Although the pain feels as if it originates in the periphery, it is actually a manifestation of abnormal sensory processing within the CNS. Manifests as: Hyperalgesia (extending beyond region of injury) Allodynia Prolonged pain after transient stimulus (persistent pain) Spread of pain to uninjured tissue (referred pain) Can persist long after healing of the injury in chronic pain states. Maladaptive. May result from inadequately-treated acute pain.

Neurotrophic hypothesis of depression

Increased stress hormone levels decrease in brain-derived neurotrophic factor (BDNF) hippocampal cell atrophy and reduced NT activity in the hippocampus. Antidepressants appear to: improve BDNF activity growth and survival of neurons in the hippocampus. promote growth factors in the hippocampus, leading to neurogenesis.

Ionotropic Receptors, also known as ligand-gated ion channels, directly activate ion channels

Ionotropic receptors have: A ligand-binding site for neurotransmitter A central pore with specific ion selectivity Rapid activation Ability to rapidly change membrane potential to either depolarize and create an excitatory postsynaptic potential (EPSP) or hyperpolarize and create an inhibitory postsynaptic potential (IPSP).

2 classes of neurotransmitter receptors (on postsynaptic cell)

Ionotropic receptors: neurotransmitter binding directly opens an ion channel and changes the postsynaptic membrane potential - rapid signaling Metabotropic receptors: neurotransmitter binding activates a G protein, resulting in second messenger production and/or ion channel opening - slower signaling Ionotropic receptors are channel proteins that open when a neurotransmitter binds to them. B, Metabotropic receptors activate intracellular signaling cascades that generate second messengers in the cell when the neurotransmitter binds.

Drugs of abuse can alter dopamine neurotransmission

Methamphetamine alters dopamine (DA) neurotransmission in two ways. 1. It enters the neuron by passing directly through neuronal membranes and can enter vesicles that normally carry DA. Once in the vesicles, methamphetamine causes the vesicles to exocytose DA surge of pleasure, exhilaration. 2. Methamphetamine also blocks the DA reuptake transporter from returning DA back into the presynaptic neuron, thus causing sustained increased DA in the synapse. *It is also thought that methamphetamine can inhibit DA autoreceptors. Over time, the brain responds by reducing the number of DA receptors and increasing the number of DA transporters. This drug tolerance, as well as a brain that doesn't respond well to other types of reward or pleasure.

Amine Hypothesis of Depression

It was originally thought that depression was a deficiency of serotonin and/or norepinephrine. But... antidepressants produce immediate increases in amine NT transmission, and yet their mood-elevating properties require weeks of treatment. So depression cannot simply be the result of a deficit of serotonin and/or norepinephrine. It is now thought that increases in the amount of synaptic amines brought about by antidepressants produce secondary, downstream neuroplastic changes that take longer and involve transcriptional and translational changes in receptors and how they respond to 5-HT and NE.

Epidemiology of Depression

Lifetime Incidence of major depressive disorder (MDD): 20% in women and 12% in men Incidence of 2% of children and 4-8% of adolescents Lifetime Prevalence of MDD: Major Depressive Disorder ~ lifetime prevalence of 3-13% (men) and 7-21% (women) World Health Organization has identified MDD as the leading cause of disability worldwide. Most episodes of depression do resolve; however, majority of those who recover will experience recurrences. Average duration of an episode of MDD is 30 weeks. Approx. 20-25% of patients will suffer from chronic depression.

Norepinephrine nuclei

Locus ceruleus (in the pons) is the main norepinephrine nucleus related to behavior, with wide projections to all cortical regions, and to cerebellum and spinal cord Implicated in arousal and awakening Increases attention Stress-mediated activation Potentially implicated in ADHD and PTSD Mood and affect Pain modulation

Types of Neurotransmitters

Major neurotransmitters: Amino acid: glutamate (excitatory) gamma aminobutyric acid (GABA - inhibitory) Others... Amine: Dopamine Norepinephrine Serotonin Others... Acetylcholine Other classes Nitric Oxide Peptides (example: Substance P)

Neuropathic pain

Maladaptive pain Originates from direct injury or irritation of nerves, resulting in disturbance of function or pathologic change Peripheral vs. central Depends on where the lesion occurs Described as: burning, stinging, numbing, tingling, electric, shock-like. (Classic descriptions of neuropathic pain.)

Metabotropic receptors have 7 membrane-spanning regions (GPCRs)

Metabotropic receptor characteristics: G protein coupled receptors with binding site for NT Work through enzymes that generate second messengers (cAMP, IP3/DAG, cGMP) Second messengers produce slower changes in membrane potential (depolarization or hyperpolarization) by opening or closing an ion channel. Second messengers can also produce additional intracellular changes such as: altered gene expression for receptors Intracellular enzyme activation These effects are also slower than ionotropic receptor effects G proteins can also directly couple to ion channels in some cases, but in general, you should think of the metabotropic receptors as acting indirectly, as opposed to direct-acting ionotropic receptors. In all events, metabotropic = slower

Brain function and dysfunction in epilepsy

Neurons are organized in complex networks - many circuits involve synaptic links between the thalamus and the cortex Within a network, a wave of excitation is often followed by a wave of inhibition, due to the presence of inhibitory neurons using the neurotransmitter GABA. If sufficient numbers of neurons fire together, are then inhibited, then fire again, the resulting synchronized depolarization and hyperpolarization can be detected as large waves on the EEG During a seizure, the synchronized activity is inappropriate (abnormal) and excessive. Groups of neurons are hyperexcitable, either by too much excitation or too little inhibition; balance between the two states is lost. An EEG recording during a focal seizure may show just a few leads with synchronized electrical activity An EEG recording during a generalized seizure reflects much more widespread activity Worst case scenario - severe, treatment-refractory, status epilepticus . . . Brain death

Therapeutic approaches to depression

Nonpharmacologic evidence-based approaches: Psychotherapy/family therapy/counseling Electroconvulsive therapy (ECT) Cognitive behavioral therapy (CBT) Transcranial magnetic brain stimulation Vagal nerve stimulation Deep brain stimulation Phototherapy Exercise Others...

Quick A&P Review: Pain

Primary somatosensory cortex: In postcentral gyrus of parietal lobe Receives sensory and proprioceptive info from skin, muscles, joints and tendons. Localizes pain. Somatosensory Association Cortex: Posterior to primary somatosensory cortex Interprets / understands pain Pain can be localized because nociceptor pathways are kept in a specific anatomical order in the spinal cord and somatosensory cortex dermatomes and the somatosensory "homunculus" Dorsal horn of the spinal cord: Grey matter; located dorsally Receives sensory information Afferent neurons: Sensory neurons that transmit impulses from skin or internal organs toward the CNS. Primary afferent neuron: The first neuron in the somatosensory pathway. Dorsal root ganglion: An enlarged area of the dorsal root where the cell bodies of afferent neurons are located.

Nociceptive Pain

Nociceptive pain results from tissue damage or potentially tissue-damaging stimuli. Pain signal starts in nociceptors. Two types of nociceptive pain: Somatic Pain Originates from receptors in skin, muscles, etc. Well-localized Visceral Pain When internal organs swell, stretch or become damaged Poorly localized

Nociceptors

Nociceptors are sensory receptors in the skin, muscle, joints, connective tissue and some viscera that selectively respond to noxious or potentially tissue-damaging stimuli. Are free (non-encapsulated) nerve endings of primary afferent nerve fibers (axons) in peripheral tissues. An important property of nociceptors is that they can be sensitized: their excitability can be increased as a result of tissue damage and inflammation. Sensitization = a reduction in the threshold at which the nociceptor responds to a noxious stimulus and an increase in the magnitude of that response.

Assessment of Pain

P - provokes/palliates? Q - quality? R - radiates? S - severity/intensity? T - temporal factors? -FACES scale

Amygdala

Part of the limbic system Controls autonomic responses associated with fear, arousal, stress, formation of memories of emotional events Activated when a person recalls emotionally charged memories, Changes in amygdala volume and activity have been observed in depressed patients. Most consistent change: increased amygdala activity. Has been observed to continue even when depression has resolved or is in remission. Communicates with thalamus and hypothalamus, hippocampus, other areas of the brain.

A&P Reminder: Pain

Recall from A&P lecture on the central nervous system: Ascending sensory pathways involve 3 neurons that communicate serially: First-order neuron = the primary afferent neuron. Synapses with the Second-order neuron at the dorsal horn. This neuron decussates and travels via the anterolateral tract to the thalamus, where it synapses with the Third-order neuron, relays pain signal to the somatosensory cortex, which will localize and interpret the pain.

Thalamus

Receives filtered sensory information via the reticular activating system (RAS) and relays it to the cerebral cortex. (More on the RAS shortly.) Passes fear-provoking sensory information rapidly to the amygdala and from there to the RAS. Links sensory input to pleasant and unpleasant feelings. Also plays a significant role in arousal, wakefulness and alertness. Post-mortem studies of severely depressed patients have shown an increased size of the part of the thalamus involved in emotion, as well as an increase in the number of neurons in this region.

Patho of Stress and Anxiety: The RAS

Receives sensory input from multiple sources, including the thalamus (mediated by amygdala). Can prioritize sensory input; filter Sends a continuous stream of impulses to cortex, either directly or via the thalamus, and to the hypothalamus. Neurotransmitters include Ach, 5-HT, NE and DA Can upregulate alertness, but can also downregulate it to allow sleep Also plays a role in interpreting pain. Circuit: Input (stimulus) RAS Response

Post-ictal phase

Recovery period after the seizure; time between the end of an epileptic seizure and return to baseline.

What is nociception?

Refers to the process by which information about tissue damage is conveyed to the central nervous system (CNS). Direct stimulation of afferent neurons due to tissue injury, or stimuli indicating potential injury or tumor infiltration of skin, soft tissue or viscera. Proportionate to the stimulation of the nociceptor. More tissue damage more pain. 4 basic processes: Transduction Transmission Perception Modulation

Pain's Multi-dimensional Components

Sensory-discriminatory Motivational-affective Cognitive-evaluative Unremitting pain can affect all aspects of quality of life

Serotonergic nuclei

Serotonin neurons are found in "raphe" nuclei, located at all levels of brainstem - pathways target all of cerebral cortex Possible role in arousal, awakening, food intake Mood and affect Pain modulation

Sources of neuronal INHIBITION

Sleep, particularly slow-wave sleep, is a time of decreased responsiveness to excitatory stimuli, although seizures do sometimes occur during sleep At the cellular level: Opening of channels permeable to potassium or chloride Activation of receptors for the inhibitory neurotransmitter, GABA.

Epidemiology of anxiety disorders

Social phobia - lifetime prevalence of 3-13% Panic disorder - lifetime prevalence of 2-3% Generalized anxiety disorder (GAD) - lifetime prevalence of 4-7% More than 80% of patients with GAD have comorbid depression, dysthymia, or social phobia Comorbid substance abuse is common Prevalence of GAD in children and adolescents ranges from 3-5% OCD - 2-4% lifetime prevalence PTSD - 1-9% lifetime prevalence The female-to-male ratio for any lifetime anxiety disorder is 3:2 Most anxiety disorders begin in childhood, adolescence, and early adulthood; however, anxiety is also common in geriatric patients.

2. Transmission

Stimulated nociceptors transmit impulses to the CNS by means of specialized sensory fibers Primary sensory fibers include: Aδ fibers: large, myelinated fibers involved in fast transmission of sharp, stinging, and highly localized pain C fibers: small, unmyelinated fibers involved in slower transmission of dull, aching, and poorly localized pain that lingers Most sensory afferent pain fibers enter the spinal cord by way of the posterior nerve roots Cell bodies of pain neurons located in the dorsal root ganglion of the spine. Pain signals transmitted by afferent fibers enter the spinal cord through the dorsal horn, synapse on second order neurons, and then cross the cord (decussate) and project centrally in the anterolateral tract Neurotransmitters that bind N-methyl-D-aspartate (NMDA), AMPA receptors in spinal cord are released. Signal terminates in thalamus, which acts as relay station to cortical regions. Pain signals travel in a similar way as other sensory information. 1. 1st order neuron (primary afferent) with cell body in the dorsal root ganglion, carries pain signal from the site of injury to the dorsal horn. 2.Synapse of 1st order neuron with 2nd order neuron in the dorsal horn of the spine. 3. 2nd order neuron decussates, travels up the anterolateral tract to the thalamus. 4. Synapse of 2nd order neuron with 3rd order neuron in the thalamus. 5. 3rd order neuron in the thalamus relays pain signal to somatosensory cortex. Many neurotransmitters and neuropeptides involved in synaptic transmission at the spinal cord level Substance P, glutamate, calcitonin gene-related peptide (CGRP), others - all involved in transmission of pain signal. Substance P is a peptide neurotransmitter. It contributes to nociceptor excitation and sensitization and also contributes to inflammatory pain by inducing release of histamine from mast cells.

Classifying Pain

Temporal Acute Chronic Etiology Cancer Non-malignant Pathophysiological Nociceptive Neuropathic

Brain electrical activity during waking and sleep

Tens of thousands of neurons may be having action potentials at any given time Awake - widely distributed activity; some groups of neurons may have synchronous activity, but there is not synchronous activity in large areas of the brain. Asleep - activity is more synchronized - greater numbers of neurons are firing, but in fewer places in the brain; there is still not synchronous activity in large areas of the brain. ' The EEG captures brain activity

Pathophysiology of Stress and Anxiety

The Reticular Formation: a set of interconnected nuclei that are located throughout the brain stem. The reticular formation has two components: The ascending reticular formation is also called the reticular activating system (RAS). It is responsible for the sleep-wake cycle and mediates alertness. It receives (and filters) sensory inputs. This part of the RAS projects to the thalamus, which also plays a role in wakefulness, and which also sends inputs to the RAS. From the thalamus, information is sent to the cortex. Can also directly communicate with the cortex. The descending reticular formation is involved in posture and equilibrium as well as autonomic nervous system activity. It receives information from the hypothalamus. One theory of the pathophysiology of stress and anxiety: for reasons that are not clear, in some people and/or situations, the Input/Stimulus RAS Response circuit can become stuck in an "on" position, generating constant stimulation of alertness, in addition to autonomic response (increased heart rate, etc.). The hippocampus also plays a role in remembering the stimulus.

The GABAB (metabotropic) receptor - G-protein coupled, links to ion channels, but not through a second messenger.

The drug baclofen is an agonist at GABAB receptors and is used in the treatment of muscle spasms associated with disorders such as multiple sclerosis.

Epilepsy statistics

The fourth most common neurological condition (after migraine, stroke and Alzheimer's) 150,000 new cases annually in the US More than 65 million people worldwide have epilepsy, > 2 million people in the US have epilepsy One-third of patients have uncontrolled seizures because no available treatment works for them. Risk factors in adults are only identified in about 40% of cases, the remainder are idiopathic

Important to keep in mind

The key role that sodium plays in the generation and propagation of an action potential. Without sodium, pain signals would not be transmitted to the CNS.

Glutamate neurotransmission

The principle excitatory neurotransmitter of the CNS - responsible for most rapid transmission including sensory and motor processing, vision, hearing, and consciousness Ionotropic receptors include AMPA, NMDA, others Contributes to learning and memory through NMDA receptors. After reuptake, immediately converted to glutamine by glial cells, which is then sent back to presynaptic terminal. Or glutamate is repackaged into vesicles at presynaptic terminal.

GABA Neurotransmission

The principle inhibitory neurotransmitter of the CNS GABAA, GABAB or GABAC receptors on postsynaptic cell Similar to glutamate, after reuptake, GABA is converted to glutamine in glial cells and returned to the presynaptic neuron.

Acetylcholine (the first neurotransmitter identified)

The role of acetylcholine was first discovered in the peripheral nervous system: Neurotransmitter of all motor neurons Neurotransmitter of all autonomic preganglionic neurons Parasympathetic Sympathetic Neurotransmitter of parasympathetic postganglionic neurons Neurotransmitter of a few sympathetic postganglionic neurons (sweat glands) Synthetic enzyme: choline acetyltransferase (CAT) Inactivation enzyme: acetylcholinesterase (AChE)

Risk Factors for Developing Epilepsy

Traumatic brain injury (TBI) Brain tumor Stroke CNS infections Dementia Hypoxia Down Syndrome Cerebral Palsy Autism Migraine with aura, particularly in children Family Hx of epilepsy, esp. family Hx of generalized seizures Febrile seizures that last longer than expected Seizure in first month of life Gene mutations Not everyone has an identifiable cause of epilepsy.

Seizure

a single occurrence of signs and/or symptoms due to abnormal excessive and synchronous neuronal activity in the brain. results when a sudden imbalance occurs between the excitatory and inhibitory forces within a network of neurons in favor of a sudden-onset net excitation Transient (usually) Paroxysmal (= sudden) A group of neurons are abnormally hyperactive and hypersynchronous form an epileptogenic focus, which is the area of the brain from which the seizure originates. Epileptogenic focus functions autonomously, causing excessive paroxysmal electrical discharges. Electrical activity can spread to neighboring groups of neurons and in some cases, to distant neurons. Results in disturbances of motor control, sensation, behavior, consciousness, autonomic function. Seizures have been described as "an electrical storm in the brain".

3. Perception

When brain interprets pain as "painful", unpleasant Impulse becomes a conscious perception of pain Likely brain structures involved: Reticular system - autonomic response Somatosensory cortex- localization and interpretation/characterization Limbic system - emotional and behavioral Pain threshold—level of pain stimulation required to be perceived Pain tolerance—degree of pain an individual is willing to bear before seeking relief Varies among individuals

Prodrome

a difficult to describe feeling that a seizure may occur - can occur minutes to hours before the seizure. Not considered to be part of the seizure. Anecdotal evidence of "seizure alert dogs" that have the ability to detect prodromal signals and can alert the person that a seizure is about to occur. No solid research about this yet. But some dogs can be trained to alert others when someone is having a seizure.

Epilepsy syndromes

clustering of findings of seizures with other clinical phenomena define specific epilepsies. Incidence may be unique to a given age group; in some cases a specific gene mutation is the cause Benign familial neonatal epilepsy, early myoclonic epilepsy, West syndrome (infancy), Dravet syndrome (infancy),and others

Focal seizure symptoms

depend on which region of the brain is affected

Modes of neurotransmission differ between neurotransmitter families

fast transmission: glutamic acid, Ach, glycine, GABA; most commonly ligand gated channels, but can be through second messenger systems slow transmission: biogenic amines and peptides; most commonly through second messenger systems but can be through ligand gated channels

The inhibitory neurotransmitter gamma aminobutyric acid (GABA) is synthesized from

glutamate

Automatisms

purposeless, repetitive motor activity seen during some types of seizures. Examples include: repeating the same word(s) over and over, picking at fabric repeatedly, smacking lips, etc.

Structure of the Amine NTs

serotonin, dopamine, norepinephrine; all have an NH2 group

Ictal phase

the period of time from the first S/Sx (including the aura) to the end of the seizure activity. Correlates with electrical seizure activity in the brain.