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Chapter 11: Opioids - Coggle Diagram

- - - - relieves craving
      - requires daily supervised admin
    - - normal euphoric effects of heroin are reduced, reducing likelihood of relapse
        
        Cross tolerance becomes a PROBLEM when patients need analgesia in the ER
  - - - BUT, if crushed and injected, naloxone BLOCKS buprenorphine's euphoric effects
  - - - designed to help severely opioid-dependent people who are resistant to MAT
        
        provide heroin at very specific times and very specific doses to try to sustain that stability and withdrawal symptoms
- - - - Natural narcotics
        
        opium
        
        morphine
        
        codeine
        
        thebaine
      - Semisynthetic narcotics
        
        From morphine
        
        hydromorphone (dilaudid)
        
        heroin
        
        From thebaine
        
        etorphine
        
        oxycodone (percodan)
      - Totally synthetic narcotics
        
        pentazocine (Talwin)
        
        meperidine (demerol)
        
        FENTANYL
        
        methadone (dolophine)
        
        LAAM
        
        Propoxyphene (Darvon)
      - Endogenous opioids
        
        enkephalins
        
        ENDORPHINS
        
        dynorphins
        
        endomorphines
  - - - more lipid soluble (readily absorbed)
      - converted to morphine in brain
      - 2-4x stronger than morphine when delivered IV
      - PO: heroin and morphine are equipotent
  - - - withdrawal occurs 8 hours after taking the drug
  - - - body temp and blood pressure fall, pupils become constricted (small pupils), respiratory failure
- - - - in animal studies, ACUTE pretreatment with opioids LOWER the threshold ICSS (enhances brain reward system)
    - - opoids injected into the VTA increase DA cell firing
        
        increases release of DA within the NAcc
      - BUT lesioning of DA neurons DOES NOT ABOLISH heroin self-admin
      - opioids increase VTA cell firing by INHIBITING inhibitory GABA projections
        
        leads to increased firing and greater DA release in the NAcc
  - - - neuroadaptive state: in response to longterm occupation of opioid receptors
      - when drug is no longer present, cell function returns to normal and OVERSHOOTS basal levels
        
        withdrawal symptoms: rebound hyperactivity
    - - Heroin (IV): peak is 48-96 hours after last use
        
        withdrawal is complete in 7-10 days
        
        at the point when abstinence signs end, user is considered "detoxified"
      - Methadone (PO): gradual increase over several days and gradual decrease over several weeks (TAKES LONGER TO RECOVER BUT WITHDRAWAL SYMPTOMS ARE MORE MODERATE)
  - - - symptoms
        
        low energy, irritability, anxiety, agitation, insomnia
        
        hot and cold sweats, goose flesh
        
        abdominal cramping, nausea, vomiting, diarrhea
  - - - enhances channel function
      - makes it easier to activate and contribute to tolerance via activation of nitric oxide synthase
- - - - opioids exert nearly all of their clinically relevant actions through stimulation of m-receptor
        
        m receptor has high affinity for morphine and related drugs
        
        mediates the reinforcing and rewarding effects of opioids
        
        m-receptor KO mice:
        
        DO NOT self admin opioids
        
        do not exhibit conditioned place preference for opiodis
        
        do not show signs of physical dependence
        
        analgesia, respiratory depression, and constipation are ABSENT
        
        Location of m-receptors reflect the effect of opioids
        
        ANALGESIA: medial thalamus, periaqueductal gray, median raphe, locus coeruleus, spinal cord
        
        POSITIVE REINFORCEMENT: VTA, nucleus accumbens
        
        CARDIOVASCULAR AND RESPIRATORY DEPRESSION, COUGH CONTROL, NAUSE: brainstem
    - - Gi: inhibits adenylyl cyclase
        
        reduction in cAMP
        
        important in understanding the CHRONIC effects of opioids: tolerance, dependence, withdrawal
      - K+ channel opening, Ca++ channel closing
        
        ion channel effects are responsible for ANALGESIC effects
  - - - most synthesis occurs in rough ER
      - secretory granules in Golgi (filled with peptide) bud off and are transmitted to nerve terminal
    - - violates Dale's Principal that states only 1 NT per synaptic vesicle
    - - Prodynorphin --> dynorphin
      - *Pro-opiomelanocortin (POMC) --> beta-endorphin
      - Proenkephalin --> enkephalin
      - Proniciceptin/orphanin FQ --> nociceptin
    - - Postsynaptic inhibition: receptors activate a G protein that opens K+ channels
      - Axoaxonic inhibition: receptors activate G proteins that close Ca++ channel
      - Presynaptic autoreceptors: activate G proteins and reduce release of a co-localized NT
- - - - Within spinal cord
        
        inhibit the projection neuron (projection neuron carries pain signal to higher brain areas)
      - descending pathways from PAG
        
        treatment of chronic pain with electrical stimulation of the PAG (PAG has a lot of endogenous opioids and m receptors)
        
        tolerance occurs with repeated stimulation
        
        stimulation of PAG caused cross-tolerance with opioids
        
        an opioid-like substance must be released
        
        Stimulation of PAG --> activation of 2 descending pathways that inhibit pain signal
        
        locus coeruleus --> spinal cord
        
        raphe nuclei --> spinal cord
        
        Descending pain regulation in PAG
        
        opioids REMOVE inhibitory GABA brake on descending projection TO raphe/LC
        
        opioid binds to m receptor on GABAergic interneurons --> releases projection neuron to Raphe/LC (freeing inhibition of GABA)
        
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      - higher brain sites (cortical areas): influences the emotional and hormonal aspects of the pain response