Clinical disorder treatment

Opioid effects on the body

For acute pain context

Clinical effect: Analgesia

Side effects: Nausea, constipation, respiratory depression

Abuse potential: euphoria/reward, tolerance, addiction, withdrawal

Opioid actions spinal cord and neuronal level

Spinal cord action = blocks signal ascending]

• Higher C fibre high expression (removes 2nd dull), less Aδ (somewhat affects 1st acute)

• MORs are G_i/o GPCRs on terminals, decrease NT release:
  1) βγ presynaptic = inhibit VGCCs (N-type), ↓ NT release
  2) βγ postsynaptic = opens GIRKs, hyperpolarisation
  3) α_i/o subunit = inhibits AC [minimal for analgesia]

Pain sensation and modulation

ASCENDING: Aδ and C fibres to DRG

1. Spinothalamic tract → S1 (precise info)

2. Reticulospinal → Reticular formation (motor, arousal)

3. Spinoparabrachial → parabrachial nuc/amygdala (affective)
   

DESCENDING: from PAG in midbrain
Inhibitory input
↓ via RVM
To nociceptive inputs in spinal cord DRG

Endogenous opioids

β-endorphins → [MORs and DORs, μ & δ]

Enkephalins → [MORs and DORs, μ & δ]

Dynorphins → [KORs, κ]

Opioid receptor types for different actions

Mu μ [MOR]: strong analgesia, clinically used
→ constipation, nausea, respiratory depression, cough reflex, tolerance, dependence

Delta δ [DOR]: spinal analgesia, too dangerous
→ convulsions, cardiovascular complications

Kappa κ [KOR]: mild analgesia, bit of clinical use
→ diuresis, hallucinations, dysphoria

Due to different expression profiles

Main types of opioid drugs

Natural (opiates): morphine, codeine, heroin, oxycodone

Synthetic/semi-synthetic

•  Agonists: methadone, fentanyl

• Partial agonists: buprenorphine

• Mixed action: tramadol, tapentadol

• Antagonists: naloxone, naltrexone

Efficacy in opioid action and use for overdose safety

Morphine = full agonist

• Affinity: moderate for MOR

• IE: high, strong GPCR signal

• Effects: high analgesia at low dose, becomes dangerous very quickly

VS

Buprenorphine = definite partial agonist

• Affinity: very high, can ‘kick out’ morphine

• IE: low, weaker GPCR signal

• Effects: less analgesia, need higher conc. for side effects and tolerance

Opiod and non-opioid synergistic actions

2+ drug interaction that creates a greater net effect than the sum of individual effects

NET & SERT inhibitors (enhances descending pathway)
i.e., tramadol (SERT), tapentadol (NER)

• 5HT excites ENKs (inhibitory interneurons)

• NAD inhibits projection neurons
  

NSAIDs (reduces prostaglandin production)

• Inhibits COX1/2 to reduce synthesis

• Reduced nociceptor sensitization & excitation

+ opioid agonist inhibits AC → stops all phosphorylation, reduces receptor activation

Pharmacological mechanism of opioid receptor tolerance

• Reduced signalling efficacy (weaker GPCR)

• Reduces receptor number

• Causes endocytosis (removal and inactivation)
  

→ extends to most pharmacological effects, less for constipation and pupil dilation

Opioid actions at brain level

Disinhibition of descending pathway

Inhibits PAG interneuron projections
↓ excitation to RVM
Spinal cord nociception is inhibited

Acute vs chronic pain

Acute pain: a transient, protective signal of actual or potential tissue damage. Immediate inflammation and nerve activity
= served by current analgesics

Chronic pain: persists 3+ months beyond healing (maladaptive), involving neuroplasticity, central sensitization, neuroinflammation, NT imbalances
= poorly treated, a ‘disease’ state, prevalent and costly

Current analgesics for chronic pain

• Anticonvulsants [gabapentin, pregabalin]

• VGCC blockers [ziconotide]

• Antidepressants

  • Tricyclic antidepressants (TCAs) [amitriptyline]

  • SSRIs/SNRIs [duloxetine]

• Opioids

• Tramadol [partial opioid agonist + SNRI]

• Topical drugs [capsaicin, local anesthetics i.e., lignocaine]

AND physiotherapy, psychological treatment, electrical stimulation, surgery (deafferentation)

Animal models and testing for chronic pain

Inflammatory pain → intraplanar injection

Neuropathic pain → peripheral nerve lesion, spinal cord injury, diabetes (streptozotocin), cancer, chemotherapy drugs (paclitaxel)

MEASURMENT

1. Mechanical allodynia i.e., Von Frey test, threshold force required for pain response (reflex)

2. Cold allodynia i.e., no. of pain reflex responses to acetone drop

3. Hyperalgesia assays i.e., Randall-Sellito device (threshold force), Hotplate/Hargreaves test (hot plate)

Analgesia MOA vs chronic pain adaptation

Generally → decrease ascending transmission + activate descending (releases NTs to further inhibit ascending)

Neuropathic pain → peripheral afferent injury causes:

• Hypertrophism = increased neurotrophic factors (NGF, BDNF) on unaffected nerves

  • Nerve sprouting from nociceptors, Aβ fibres

  • Abnormal (non-noxious) activation of pain circuits i.e., spinothalamic tract

• Immune response = macrophage inflation, T-cells, proinflammatory cytokines

• Ion channel expression = increased VGSCs (1.3, 1.7), VGCCs, TRPV1 (uninjured C-fibres, sense heat)

→ Reduced activation threshold, hyperalgesia, spontaneous pain (ectopic nerve activity) 

→ Central sensitisation (synaptic strengthening in spinal cord/brain)

Opioids (chronic pain treatment)

Normally activates MORs on nociceptor terminals & ascending tract
= reduced Ca²⁺ influx, reduces ascending activation

Neuropathic pain i.e., adaptive sprouting & abnormal spinothalamic innervation

• Less MOR expression on Aβ fibres (non-noxious afferents)

• MORs only expressed on ascending tract neurons

• Opioids can’t be used LT (addiction, tolerance, overdose)

Some reduction, less analgesia than for acute pain

Nociception vs pain

Nociceptor activation of Aδ or C fibres to produce a sensory response from a painful stimulus

VS

Sensory, emotional, and aversive cognitive assimilation as the stimulus is interpreted once it travels through said pathway

Chronic pain classifications

1. INFLAMMATORY: clear, obvious reason for pain state
   → ongoing nociceptor activity, tissue injury, inflammation processes

2. IDIOPATHIC: unknown cause after medical investigation
   → i.e., fibromyalgia, CRPS

3. NEUROPATHIC: lesion or disease of the nervous system
   → peripheral or central, difficult to treat and can persist post-recovery (i.e., peripheral trauma, central injury, stroke, diabetes, HIV, MS, chemotherapy)

Neuropathic pain symptoms

• Sensory abnormalities:

  • Spontaneous pain: pain or burning, in the absence of stimulation

  • Allodynia: normally innocuous stimuli is painful (light touch, brushing, cold)

  • Hyperalgesia: noxious stimuli is much more painful, reduced threshold to pain response

• Sleep disturbances

• Anxiety, anhedonia, depression

• Cognitive impairments, familial/social disturbances

• Metabolic and endocrine disturbances

Endocannabinoid system role in pain, mood, stress regulation

• Sleep and circadian rhythm (peak/trough throughout day)

• Analgesia

• Positive mood

• Energy balance

• Stress coping

• Appetite (hypothalamus = munchies)

Major phytocannabinoids MOA

Tetrahydrocannabinol (THC) = CB₁ & CB₂ orthosteric agonist

Cannabidiol (CBD) = CB₁ NAM, increases endoCBs, inhibits degradative enzymes

Medicinal cannabis, epidiolex (epilepsy), sativex (MS, neuropathic pain)

Major known hypotheses of depression

• Monoamine theory

  • Functional deficit of monoamines causes depression (‘65)

  • Hypo-NA/5HT state causes receptor hyperresponsiveness (‘80s), drugs restore NT to receptor balance

  • Receptor to NT imbalance?

• Neuroendocrine mechanism

  • HPA dysregulation causes maladaptive stress response

  • Chronic stress decreases HP inhibition, poor negative feedback

  • GCs and BDNF interfere with HP neurogenesis (↑ CRF & CORT)

• Neuroplasticity & neurotrophic hypothesis

[Neurogenesis is new neuron formation from stem cell precursors in SVZ (lat. ventricles) and SGZ (dentate gyrus)]

• 5-HT and NAD R subtypes + BDNF promote neurogenesis

• Antidepressants ↑ 5-HT and NA synthesis to enhance BDNF signalling
  → BDNF-TrKB pathway aids neurogenesis, restores network function

Stress and depression = dampened neurogenesis, neuronal loss in HP & PFC, ↓ BDNF and TrKB receptors, ↓ cell proliferation, survival, differentiation

Neural substrates + major NTs of stress and mood

Neural circuitry

• PFC and HP involved in cognition

• NAc and Amy involved in emotions

• Hyp and monoamine brainstem nuclei (DR, LC) involved in appetite and energy (vegetative symptoms)

• Major NTs: NAD, 5-HT, DA, GABA
  

HPA axis → also key regulator in mood and vegetative features
[Hippocampus, amygdala, monoamine brainstem nuclei]
↓ 
PVN of hypothalamus
↓ CRH (corticotrophin-releasing hormone)
Anterior pituitary
↓ ACTH (adrenocorticotrophic hormone)
Adrenal cortex
↓ GCs (cortisol, corticosterone)

Major classes of antidepressants

• Monoamine reuptake inhibitors

  • TCAs

  • SSRIs

  • SNRIs

  • NRIs

• Monoamine oxidase inhibitors (MAOIs)

  • Irreversible non-selective MAO_A & MAO_B inhibitors

  • Reversible inhibitors for MAO-A (RIMAs)

• Tetracyclic antidepressants

• Multimodal activity drugs 

  • SRI and 5-HT₁ full/partial agonism

Most target NAD and 5HT with ~70% effectiveness and delayed effect
→ note many contraindications, suicide risk, treatment resistance

Short vs long-term effects according to monoamine hypotheses

Short-term = increased synaptic levels of NA and 5-HT

Long-term

1. Downregulation of postsynaptic NA (β-adr), 5-HT₂
   [↓ binding sites, agonist response]

2. Increased activity/sensitivity of postsynaptic 5-HT₁ in HP

3. Desensitization of presynaptic α2-adr, 5-HT₁ (inhibitory autoreceptors)

= enhancement of monoaminergic function

↑ available MAOs + ↓ hyperresponsive Rs = optimal NT levels & sensitivity restored

Downregulation of: β2 autoreceptors, 5-HT₂ receptors, α2 adrenoreceptors

Monoamine reuptake inhibitors (TCAs, SSRIs, SNRIs, NRIs)

MOA is dose-dependent reuptake inhibition:
Blockage of presynaptic NATs and/or SERTs
↓
Increased synaptic levels of NA and 5-HT

• TCAs also block mACh, 5-HT, histamine, and α-adrenoreceptors (poor selectivity, dirty drug)

  • Highly effective, gold standard, good for severe depression

  • Narrow therapeutic index, high toxicity and overdose risk, strong potentiation of alcohol effects, respiratory depression

• SSRIs are pure and highly selective @ therapeutic dose, much safer

  • Effective in reducing anxiety, agitation, retardation

  • Good for moderate depression, less for severe

• NRIs are notably less efficacious

• MAOIs are effective in atypical depression

Monoamine oxidase inhibitors (MAOIs)

Inhibition of NA, 5-HT & DA breakdown
↓
Increased MAOs in cytoplasmic pool
↓
Increased spontaneous leakage into synapse and extracellular space
↓
Boosted MAO levels

Tetracyclic antidepressants

Blockage of α2 adrenoreceptors
↓ disables -ve feedback loop
Increased NA & 5-HT release
   +
Blockage of 5-HT_2/3 receptors
↓
Enhanced endogenous action on 5-HT₁

Multimodal action antidepressants

Blockage of presynaptic SERTs
↓
Increased 5-HT release
+
Full or partial agonism of postsynaptic 5-HT_1A/3 receptors
↓
Increased 5-HT at synapse

Clinical features of major depression

A. Vegetative symptoms (basic bodily functions)

• Significant weight loss or gain/inc or dec in appetite

• Insomnia or hypersomnia

• Psychomotor agitation or retardation

Emotional & cognitive symptoms (non-vegetative)

• Depressed mood (sad, empty, hopeless, tearful, irritable)

• Anhedonia (inability to experience pleasure)

B. Symptoms affect social and occupational functioning

C. Symptoms not due to drugs or another medical condition

Antidepressant side effects and contraindications

[Anticholinergic] blurred vision, dry mouth, constipation, sweating, urinary retention
[Cardiovascular] hypotension, tachycardia, arrhythmia
[CNS] confusion, anxiety, restlessness, insomnia, drowsiness
[Gastrointestinal] nausea, vomiting, anorexia, diarrhoea
[Endocrine] libido and potenxy

TCAs: anticholinergic, cardiovascular, CNS, gastrointestinal, endocrine

MAOIs: anticholinergic, cardiovascular, CNS, gastrointestinal, cheese rxn

SSRIs: CNS, gastrointestinal, endocrine, ↑ violence/aggression, suicide

Other: CNS, gastrointestinal, endocrine, ↑ serum cholesterol

Overall high contraindications, especially for TCAs and MAOIs
→ avoid with cardiovascular disease, epilepsy, glaucoma, liver disease

Future investigations for depression treatment

• Signal transduction mechanisms (kinases, transcription factors, growth factors)

• Neurogenesis

• CRF₁ agonists to block HPA axis & centrally-mediated stress responses

Sedation vs hypnosis

A reduction in excitement, vigilance, and physiological arousal (relaxed, calm, possibly sleepy)

VS

The induction of drowsiness and sleep

Function and clinical use of sedatives

Function and clinical use of hyponotics

Function and clinical use of anxiolytics

Synaptic & regional MOA of benzodiazepines

Synaptic → mainly acts on GABA_A but a dirty-drug involving other subunits:

• Binds to α-γ interface and blocks binding site (α_{1-3, 5} & γ₂)
  α₁ = sedative/hypnotic, anticonvulsant
  α_2/3 = anxiolytic
  α_3/5 = myorelaxant

• Frequency mechanism, increasing GABA affinity and no. of openings

• Same amount of GABA allows more Cl^- entry = more inhibition

Clinical effects:

• Hypnotic, sedative & anxiolytic

• Amnesic, strange sleep behaviours

• Antiepileptic

Brain regions (wide effects): Amy, PFC, Hyp, STR (+ bed nucleus), HP

Sedative-hypnotic vs anxiolytic drug classes

Sedative-hypnotics can either target a sleep-modulatory system or increase major inhibitory NTs (more effective)

• Primarily increasing inhibitory effect of GABA

• Leverage dose-dependance to completely reduce CNS activity

• Used for insomnia and surgery (sedation or pre-anaesthesia)

Anxiety disorders result from amygdala dysregulation (plasticity issues, upregulated activity)

• Also modulate GABA_A receptors for reduced excitation at a lower dose to avoid drowsiness

• α2 implicated with anxiety in the amygdala
  → alprazolam & clonazepam have higher α2 affinity

• SSRIs are also used due to widespread 5HT axonal projection

Other i.e., pregabalin, busiprone, psychedelics, ketamine

Problems with benzodiazepine use

• Maximum use should be 1 month

• Stopping use must be tapered (cold turkey can cause seizures, headache, twitching, nausea, insomnia)

• Dependance liability (high efficacy, same class as high potency opioids)

• Strange sleep behaviours, amnesia, falls

• Combination with other sedatives dangerous

• Major overdose and dependance risk

Recreational/controlled vs compulsive drug use (addiction)

Major drugs of abuse stimulate dopaminergic activity in mesolimbic pathway

• DA neurons in VTA project to NAc

• Associated with variety of learning processes, natural rewards

• Intermittent vs frequent use differentiates controlled vs compulsive

Addiction occurs when drug use continues in spite of serious potential or actual harm to the user or others

• Complex brain disorder (genetic, neural, environmental, social causes)

• Physical symptoms + compulsive behaviours/cognitive symptoms

• Changes in regional activity (PFC, Amy & HP, NAc & VP, OFC)

Cellular adaptations producing addiction (withdrawal changes)

Tolerance = decreased response to the same dose

• Receptors become less responsive and/or internalized

• Pace varies across brain regions (some can still have high occupancy)

• High dose in response→ more likely to drive LT processes
  
  

Counter-adaptations = causes craving and withdrawal

• Drug use consistently modifying activity outside of preferred baseline

• Neurons develop processes/compensation to restore normal level of functioning

i.e., development of inhibitory processes in response to an excitatory drug, opioids

- MORs are located on DA-neighbouring GABA inhibitory interneurons
- Opioid binding reduces GABA release, indirectly ↑ DA release in NAc
- Receptor activation also inhibits cAMP, acute reduction causes
  compensatory effects over 24 hrs (chronic causes hypertrophied signalling)
- Removal causes overshoot of cAMP, ↑ NT release/excitability
  = withdrawal syndrome

Treatment approaches for SUD/addiction

• Reduce cue-induced responding
  

• Alleviate withdrawal symptoms (rapid detox)

  • Drugs to reduce excitability for symptom reduction

  • High relapse rate i.e., Clonidine, BZs
    

• Long-term substitution ✓

  • Prevents withdrawal and craving without high or euphoria

  • Good for harm reduction and maintaining high functioning

  • Used with counselling and social support

• Blocking response (μ-opioid antagonist, naltrexone)

  • Occupies receptor and prevents agonist binding to prevent system activation

  • Ignores neuronal changes, poor compliance
    

• Aversive therapies
  

• Reducing drug use to reduce craving

Treatment for opioid addiction

Withdrawal symptom alleviation (rapid detox) = clonidine, benzodiazepines

Response blockers = naltrexone

Long-term substitution = methadone & buprenorphine
[long-term = reduced cue-induced drug seeking]

• Near full μ-agonist (methadone):

  • some R occupancy stops withdrawal/craving w/o intoxication

  • good dosing, long t_1/2, harm min., highly controlled (daily)

• Partial μ-agonist (buprenorphine)

  • prevents full agonists from R activation, ↓ craving/withdrawal

  • antagonist against full MOR agonists)

  • less overdose risk than methadone, no resp. depression

  • Available with naloxone to prevent people injecting it

Drug addiction (SUD)

Where drug use continues in spite of serious potential or actual harm to the user or others
→ complex brain disorder from combined genetic, neural, environmental, and social causes

Biological vs environmental contributions to SUD

Genetics → hard to dissect effect of comorbidities on data

• ~40-60% heritability and polygenic

• 17 loci associated with SUD (across substances)

  • High rate of dysfunctional DA system genes (D2, PDE4)

• 47 substance-specific loci

  • Highest heritability is alcohol

  • ADH mutations causing faster breakdown → inc. risk

  • Others include nACh or opioid receptor mutations

Environmental → particularly in opiate abuse

• External stresses, chaotic home nevironment

• Trauma and/or abuse

• Peer influence and community attitudes

• Poor school achievement

Steps in producing compulsive drug use (addiction)

1. Cue-reward learning

   • Positive/euphoria becomes linked with action/event, re-exposure to cues drives drug-seeking behaviour

   • Embedded in BLA outputs to NAc which drives motor programs

   • Faster onset of DA increase = faster reward association

2. Habitual reasoning

   • Shift from outcome-based (goal directed) to habitual (non-outcome based, compulsive) in 20-30% animals

   • Persists even if reward is devalued, punishment, freq. reduced, negative outcomes

   • Triggers activity in different regions of striatum

3. Withdrawal changes = neuroplasticity

   • Tolerance

   • Counter-adaptations

Withdrawal and LT craving from counteradaptations

Initially: opioids inhibit GABAergic cells for high DA release
Counteradaptation: hyperexcitability response
= drug removal causes higher activity than that at baseline

• GABAergic cells become highly active, inc. NT release

• Causes tight inhibition of DA and drops levels in the NAc

Negative emotions (dysphoria) + physical responses i.e.,
(restlessness, muscle/bone pain, diarrhoea, vomiting, cold flashes, kicking movements, emotional aversion)

Alcohol MOA and SUD

• Enhanced GABA/Gly transmission = increased inhibition

• Inhibition of VGCCs, glu receptors, adenosine transport

• Activation of K⁺ channels (GIRKs, BKs, KCa2s)

→ likely some kind of disinhibition to stimulate mesolimbic pathway

Alcohol SUD symptom treatment

LT craving and withdrawal characterized by profound hyperexcitation and wide range of effects

Symptoms: Delirium tremor (DTs), nausea, sweating, fever, hallucinations, confusion, agitation, aggression, seizures, death

Treatments:

• Hyperexcitation symptom alleviation (↑ inhibition)
  → Mild: carbamazepine, GABApentin, BZs
  → Moderate: BZs, barbiturates
  + beta-blockers or clonidine

• Aversive therapies (disulfram)
  → inhibits aldehyde dehydrogenase, limits breakdown cycle

• Reducing use to reduce craving
  → Naltrexone (MOR antagonist) reduces reward, modest relapse prevention
  → Psychedelics & ketamine to break cue-reward memory

Epilepsy

Complex group of disorders with an enduring predisposition to generate epileptic seizures
→ Due to: genetics, brain injury, infection, abnormal brain structures, immune, or metabolic function, can be known

Types of seizures and epilepsy syndromes

Epilepsy types:

• Focal (begins in 1 brain region)

• Generalised (whole brain hyperexcitability)

• Combined generalised & focal

• Unknown

SYNDROMES (seizure + symptom cluster)

• Dravet syndrome

• Lennoz-Gastaut syndrome

• Tuberous sclerosis complex

• Febrile seizures (fever)

= different seizure types require different drugs

MOA of antiepileptic drugs

1. Modulating voltage-gated ion channels (phenytoin, lamotrigine)
   [↑ inhibition & inactivation]
   

2. Enhancing GABA-mediated inhibition (BZs, tigabine)
   [↑ inhibition]
   

3. Interacting with synaptic release machinery (levetiracetam)
   [↓ excitation]
   

4. Blocking ionotropic glutamate receptors (perampanel)
   [↓ excitation]
   

5. Combination mechanisms (CBD, valproate)

Future anticonvulsant directions

Beyond neurons; microglia & astrocytes

• Role of neuroinflammation

• Rise of gene and immunotherapies
  → i.e., injecting a functioning channel gene for DS

• Small molecule therapies are symptomatic, not curative

• Focus on disease-modification
  = blocking epileptogenesis, slowing progression

Also: surgery, vagal nerve stimulation, ketogenic diet

Dravet syndrome

• Lifelong, begins in infancy

• Febrile trigger, progresses to severe tonic-clonic

• Developmental delays (cognitive & motor)

• Drug resistant, often requires multi

• Varying seizure types (tonic/atonic)

• Rare, few treatments available

• 15-20% SUDEP

Lennoz-Gastaut syndrome (LGS)

Causes:
→ structural (malformations from birth, brain injury/infection)
→ genetic (D120N mutation)
→ metabolic

• Drug resistant, polypharmacy

• Large genetic component, very rare

Epilepsy seizure types

Tonic-clonic: stiffening → rhythmic jerking

Absence: blanking out

Myoclonic: muscular jerking/twitching

Infantile spasms: stiffening, head/limbs moving back and forth

Anticonvulsant discovery program (Lambert)

1. Screening for targets
   (CB_1/2, GABA_A, GPR55, Cav3.1, NaVs, TRPV1)

2. Stem cell injections & zebrafish models (high throughput)
   [PTZ model: GABA_A antagonist]

3. Mice models
   (DS, LGS, west syndrome)

CBD screening for anticonvulsants

Looking to resolve:

1. Potency & efficacy

2. Reduce lipophilicity 

3. Pharmacokinetics (absorption, stability, oral bioavailability)

4. Safety (mitigate liver toxicity, DDIs)

Trigeminovascular system

Extracerebral origin = nerve + vasculature interaction

CN V projections (CNS & PNS):

• Trigeminal nerves and ganglia

• Meninges

• Major cerebral vessels

• Trigeminal nucleus caudalis

• Spinal cord trigeminocervical complex

^peripheral projections to nociceptors^

Role of 5-HT in migraines (neurogenic inflammation)

Sharp decrease in 5-HT levels during attack (perturbation of metabolism & transmission)

ANTI-MIGRAINE: role in vasoconstriction & vasodilation dilation

• 5-HT_1B: trigeminal ganglion soma

• 5-HT_1D: trigeminal axon terminal

• 5-HT_1F: trigeminal nucleus caudalis soma

^activation reduces change of receptor firing^

PRO-MIGRAINE: 5HT₂ on meningeal blood vessels triggers intracranial vasodilation
→ neurogenic inflammation & further dilation

MOA of 5-HT drugs in acute migraine treatment

Migraines

Environmental trigger (foods, beverages, chemicals, sunlight, hormones, OC)

1. Interictal phase

2. Prodrome and aura (20%)

   • Visual disturbances: blurring, blind spots, zigzags

   • Also: aphasia, chills, tremor, vertigo, paresthesia

3. Headache (<72 hrs)

   • Symptoms: unilateral, localised, throbbing

   • Also: nausea, light/sound sensitivity, frustration

4. Termination

5. Postdrome

Abortive (acute) vs prophylactic (preventative) migraine treatments

Abortative drugs are taken at the onset of an attack to stop it

Prophylactics are taken regularly to prevent or reduce attack frequency/severity

Abortative migraine drugs

• NSAIDs

  • Block COX1, ↓ inflammatory soup

  • Good for mild/moderate, only work at onset of attack

• Ergotamines

• Triptans

Neurogenic inflammation theory of migraine

POSTIVE FEEDBACK LOOP

Unknown stimuli activates…

↓ ophthalmic division

Trigeminal ganglion triggered for vasodilation

↓ CGRP, SP, NO, NKA

Pro-inflammatory effect:

1. Intercranial/meningeal vasodilation: plasma protein leakage

2. Mast cell degranulation: 5-HT, bradykinin, HIS, prostaglandin

= inflammatory soup
↓ spinal tract

Trigeminal nucleus caudalis (brainstem)

↓ trigeminothalamic tract

VPM thalamus = nausea, vomiting

↓

S1, insula, cingulate = pain

Neurogenic inflammation & peripheral sensitisation
(sterile process from innocuous stimuli)

Prophylactic migraine drugs + MOA?

• β-adrenoreceptor antagonists
  → unknown, no cardiovascular contraindications

• 5-HT₂ receptor antagonists
  → prevents 5-HT₂ induced vasodilation

• Anticonvulsants
  → reducing excitability to increase trigger threshold, dec. trigeminal transmission

• Ca_v antagonists
  → reduced cellular excitability, inc. threshold to trigger

• TCAs
  → SERT and NAT binding, increased 5-HT prevents noxious transmission

• CGRP receptor monoclonal antibodies
  → competes for CGRP binding, inhibits receptor function

Pathophysiology of schizophrenia relating to dopamine hypothesis

Presynaptic DA abnormalities

• Elevated levels, synthesis & release in key areas (NAc/Hip)

• Dysregulation from other NT deficiencies (GABA, Glu)

• Supersensitive D₂ receptors
  → blockage can reduce overactivity and alleviate psychosis

Mesolimbic = hyperactive
→ positive symptoms
(therapeutic effects)

Mesocortical = hypoactive
→ negative and cognitive symptoms
(therapeutic effects)

Nigrostriatal (dorsal) = hyperactive
→ cognitive symptoms, correlates w/ symptom severity
(ventral, movement side effects)

Tuberoinfundibular
(off-target, endocrine side effects)

LT vs ST antipsychotic effects

SHORT-TERM: blockage of D₂
(increases excitation, more chance of cell firing)

• Presynaptic autoreceptors = increase DA release

• Postsynaptic = supersensitive, decrease DA inhibition
  

LONG-TERM: dampening effect
(restores homeostasis)

• Presynaptic autoreceptors = upregulated, ↓ DA release

• Postsynaptic = upregulated, desensitised, more inhibition

Drug action of antipsychotics

USES: psychosis, treatment-resistant schizophrenia, bipolar disorder, Parkinson’s drug-induced psychosis, dementia behavioural disturbances, conduct disorder, Tourette’s

All have agonist effects at dopamine D₂ receptors

• linear correlation between therapeutic efficacy and D₂ affinity

• efficacy reached for occupancy up to 80%
  → side effects when exceeding 72/78%

Typical vs atypical antipsychotics

TYPICAL antipsychotics

• Good for positive symptoms and acute psychosis

• Don’t act on negative/cognitive symptoms (disabling)
  

ATYPICAL antipsychotics

• Good for + AND - symptoms, treatment resistant patients

• Better therapeutic efficacy, less movement side effects

• 5-HT + D₂ combination offsets side effects

• Exclusive risk of metabolic syndrome (ongoing for life)

Role of glutamate in schizophrenia

• Glutamate hypothesis: possible hypofunction of NMDA receptors leading to deficient Glu signalling

  • cortical disinhibition

  • dysregulated DA release

• Glutamate also converges onto NAc in ventral striatum (positive symptoms)

• Lower concentrations of Glu in CSF

• Inadequate excitatory signalling causing cognitive and executive deficits

• Novel drug approaches enhancing Glu activity

Neuropathology and etiology of schizophrenia

• Disorder of higher cognitive function (thought disorder)

• Neurochemical and structural abnormalities (white matter, ventricles, NTs, receptors)

• Genetic predisposition (multigenic) + altered development (natal insult) + environmental stressor (also drugs)

• Vulnerable during adolescence

Symptom profile of schizophrenia

1. Positive symptoms = excess of regular function
   (hallucinations, delusions, disorganized thought/speech)

2. Negative symptoms = reduction of regular function
   (flattened affect, apathy, alogia, avolition, anhedonia)

3. Cognitive symptoms = reduction of cognition (PFC)
   (impaired memory, impaired executive function)

Symptoms and aeitiology of Parkinson’s disease

1. Clinical triad (motor) = tremor @ rest, muscle rigidity, bradykinesia

2. Non-motor symptoms = restless legs, hyposomnia, micrographia, constipation, reduced thirst

• Progressive, idiopathic, neurodegenerative movement disorder

• Large disease burden (↓ life quality)

• No cure/disease-modifying treatments

Loss of DA in SNc neurons causes

Underactivation of direct pathway (↓ activity)

Overactivation of direct pathway (↑ activity, disinhibition)

= excess thalamic inhibition, net increase in GPi/SNr activity

Neuropathology and progression of Parkinson’s disease

1. Progressive death of dopaminergic neurons in SNc

2. Protein aggregate deposits (α-synuclein Lewy bodies, SOD1, tau)

Long preclinical phase: 10+ years where 60-80% DA neurons die
(NON-MOTOR: constipation, RBD, EDS, hyposomnia, depression)

Early phase: now identifiable, means significant progression
(NM & M: pain, fatigue, MCI, bradykinesia, rigidity, tremor)

Advanced/late: high comorbidity with dementia

(+ COMPLICATIONS: urinary, dementia, orthostatic hypotension, fluctuations, dyskinesia, dysphagia, posture unstable, freezing gait, falls, psychosis)

How is DA biosynthesis and metabolism exploited for Parkinson’s treatment

Pairing L-DOPA (DA precursor) i.e., sinemet, madopar, kinsen
with enzymes to prevent DA from:

• Peripheral breakdown → allows more BBB diffusion
  i.e., AADC, COMT inhibitors

• Synaptic metabolism → enables recycling & reuse
  i.e., MAOB inhibitors (rasagiline, selegiline, safinamide)

L-DOPA treatment of Parkinson’s disease

Replacing the loss of dopamine in SNc via precursor

• DA has poor BBB penetrability vs L-dopa can be orally administrated

• Diffuses into target neurons with specific conversion enzyme
  → dopa decarboxylase

• Packaged into vesicles to replace stores
  → facilitates release @ constant rate
  

Clinical response changes over time due to progressive neuronal death
1-3 years: ‘Clinically observable symptoms’
(enough neurons for constant DA release, plasma fluctuations)
4-6 years: ‘End of dose akinesia’
(wavering, enters red zone, wears off after 6hrs, inconsistent)
6-10 years: ‘Hyper/dyskinesias’
(off-target dyskinesias = too high/low, dose/freq. increase, minimal neurons)

Other drug treatments for Parkinson’s disease

All are SYMPTOMATIC, not curative

• L-DOPA (oral, inhaled, fast/slow release tablets, infusion via injection)

• Dopamine agonists: mimics DA itself

  • post-synaptic interaction w/ receptors (not DA neurons)

  • longer plasma t1/2, lower motor complications in early stages

  • more side effects

• Anticholinergics: targets overactive cholinergic neurons in indirect pathway

  • mostly post-synaptic mAChRs

  • dampening causes off-target effects (nausea, vomiting, psychiatric, fluctuations, doses shortening, dyskinesia)

Clinical features of dementia

A symptom cluster caused that impairs quality of life & normal functioning
i.e., diseases: AD (70% of cases), Parkinson’s dementia, Lewy body disease, micro cerebral ischemia, dementia from stroke, vascular dementia

Progressive decline in mental function

1. Initial subtle changes in memory and cognition
   (misplacing items, forgetting appointments, dysnomia)
   

2. Abnormal behaviour and personality changes
   (spatio-temporal orientation, forming new memories, altered judgment, moodiness, depression, apathy)
   

3. Eventual institutionalization
   (dysphasia, aphasia, apraxia, loss of knowledge, paranoia, psychosis, disorientation, overt parkinsonism)

• memory decline

• intellectual function

• sleep disturbances

• motor incoordination

• ± behavioural & personality changes

Pathology of Alzheimer’s Disease

Risks: age, sex, family history, maternal age at birth, repetitive head trauma

1. Cerebral atrophy
   → causes ventricular enlargement
   

2. Neuronal loss (ACh neurons) & gliosis (microvascular scarring)
   → hippocampus, cortex, amygdala, olfactory system, nucleus basalis
   

3. Amyloid plaques
   → extracellular aggregates of Aβ peptide (neocortex, hippocampus)
   ^APP cleaved by β-secretase creates diff. lengths of Aβ peptide (42)^
   

4. Neurofibrillary tangles
   → abnormal bunches of pTau filaments in neurons

*don’t know if plaques and tangles are toxic or attempting to absorb toxicity 

Neurochemistry of Alzheimer’s Disease

Acetylcholine: deficit in neurotransmission

• Loss of cells in nucleus basalis (attention, arousal, memories)

• ↓ synthesis, ↓ degradation, ↓ choline uptake

• General decline in ACh transmission
  

Amines: cell loss in synthesizing regions

• Loss of cells in locus coeruleus (↓ NA)

• Loss of cells in raphe nuclei (↓ 5-HT)

• Cause of mood disorders
  

Glutamate: excess causing excitotoxicity [theories]

• Reduction in GLUTs (not enough synaptic clearing)

• Aβ interference with synaptic Glu release

• Overstimulation of Glu receptors

Genetic factors contributing to Alzheimer’s Disease

>95% cases are sporadic with no genetic basis

MULTIFACTORIAL

• Amyloid precursor protein (APP): chromosome 21
  → trisomy causes down syndrome = early onset AD
  

• Presenilins (PS1, PS2): chromosome 1, 14
  → γ-secretase complex includes presenilin
  → affects APP processing, mutations can create more Aβ42
  

• Apolipoprotein E (apoE): 3 alleles (ε2, ε3, ε4) dictates disease onset
  → epsilon genes, also involved in cholesterol trafficking
  → apoE2 is protective, 4 increases risk (earlier onset)
  → high cholesterol can disrupt APP processing

Current Alzheimer’s Disease treatments

Cholinesterase inhibitors (small molecules preventing breakdown)

• Firstline treatment, overall bad GI side effects

• Only relieve symptoms, don’t halt progression

• i.e., rivastigmine, donepezil, galantamine
  

NMDA antagonists (glu hypothesis, reduces excitability)

• Side effects: dizziness, headache, constipation, confusion
  

Antidepressants & neuroleptics (for mood disturbances)

• Modulating NA and 5-HT transmission

• Aids symptoms but no impact on pathology

Experimental approaches for Alzheimer’s Disease treatments

β-secretase (BASE) inhibitors
→ inhibit enzyme to prevent formation of Aβ plaques, bad side effects

γ-secretase inhibitors
→ preventing Aβ plaques by binding to catalytic site, bad side effects
(NSAIDs also disrupt secretases)

Statins to reduce cholesterol biosynthesis
→ elevated cholesterol disrupts APP processing, earlier disease onset

Metal-chelating antibiotics
→ zinc and copper promote plaque formation, only worked in animals

Immunotherapy (immunisation w/ β-amyloid)
→ monoclonal antibodies to bind and clear plaques
→ only worked/protective in mouse models (toxic to humans)

Nootropics aka cognitive enhancers
→ aids learning & memory, information between hemispheres, resistance to chemical/physical assault, lack of peripheral, sedative or neuroleptic effects)

Types of dementias

Treatable dementias: due to cause or situation, if rectified can be reversed

• Disease

  • General paresis from syphilis

  • Endocrine-metabolic (myxedema, Cushing’s, hepatic encephalopathy from liver failure)

• Nutritional deficiency (Wernicke-Korsakoff; thiamine, pellagra; B3/niacin, B12)

• Brain tumors & trauma (head injury, ↑ intracranial pressure)

• Psychiatric illness (pseudodementia)

• Chronic drug intoxication (alcohol, barbiturates)
  

Degenerative dementias: neuronal changes, poorly understood, no cure

• Alzheimer’s disease

• Dementia w/ Lewy bodies

• Vascular dementia

• Frontotemporal dementias (Pick’s disease)

• Prion disease (CJD)

• Huntington’s disese

• Thalamic dementia

• Parkinson’s disease