Chapter 11: The Opioids Flashcards
Opioids
Class: narcotic analgesics
*reduce pain without producing unconsciousness but do produce sense of relaxation and sleep
Opiate narcotics are derived from […]
Opiate narcotics are derived from poppy plant
Natural Narcotics (Opiates)
Opium
Morphine
Codeine- less analgesic effects and fewer side effect than morphine
Thebaine
Opioids consist of:
Semisynthetic narcotics
Synthetic narcotics
Endogenous neuropeptides
Semisynthetic narcotics
Derived from morphine:
- Heroin
- Hydromorphone (Dilaudid)
Derived from thebaine:
- Oxycodone (Percodon)
- Buprenorphine (Buprenex)Synthetic narcotics
Pentazocine (Talwain) Meperdine (Demerol) Fentanyl (Sublimaze) Methadone (Dolophine) LAAM Propoxyphene
Endogenous Neuropeptides
Enkephalins Endorphins Dynorphins Endomorphins Nociceptin/ orphanin FQ
Partial Opioid Agonists
Pentazocine (Tolwin)
Narbuphine (Nubain)
Buphrenone (Beprenex)
Pure antagonists
Naloxene (Narcan)
Nalorphine
Endogenous opioids are derived from […]
Endogenous opioids are derived from pro-peptides
- POMC
- Proenkephalin
- Prodynorphin
- Pronociceptin/ophanin FQ
POMC
Beta- endorphins (B-END)
Mu and delta receptors
- found in pituitary gland and releases variety of hormones
Proenkephalin
Met- and leu-enkephalin (ENK)
Delta receptors
Inhibited by peptidases RB-101, RB-120, RB-3007
Prodynorphin
- a- and B-neoendorphin
- dynorphin (DYN) A and B
- kappa receptors
Pronociceptin/ ophanin FQ
NOR receptors
Phenylalanine and glutamine
BU08028
Dual MOR-NOP-R agonist
There are 4 opioid receptors
High opioid affinity (highly selective)
- Classical subtypes: mu, delta, kappa
- NOR
*biased agonism
Mu receptors
- high affinity for morphine
- medial thalamus, peri aqueduct all gray (PAG), median raphe, and clusters in spinal cord
- feeding and positive reinforcement
- cardiovascular and respiratory depression
- nausea and vomiting
- sensorimotor integration
Delta receptors
- forebrain: neocortex, striatum, olfactory areas, substantia nigra, and nucleus accumbens
- olfaction, motor integration, reinforcement, and cognitive function
- similar to MOR
kappa receptors
- high-affinity binding to ketcyclazocine
- striatum, amygdala, hypothalamus, pituitary
- pain perception, gut motility and dysphoria
NOR
- cerebral cortex, amygdala, hippocampus, and hypothalamus
- analgesia, feeding, learning, motor function, and neuroendocrine regulation
Opioid receptors are […] receptors
Opioid receptors are GPCR receptors
- inhibitory
- increased gk- opens channels
- decreased gca- closes channels
- adenylyl cyclase- inhibits activity (longer term effects)
Opioid receptor isolation, transfection, receptor cleaning, and molecular sequence
- Specific nucleic acid sequence
- AA of protein can be identified
- Transfected cells used to study intracellular changes
- In situ hybridization: visualize cells that synthesize receptors
Neuropeptides reduce synaptic transmission
*inhibition of endogenous opioids
- Postsynaptic inhibition: open K+ channels
- Axoaxonic inhibition: close Ca2+ channels (usually GABAergic neurons)
- Presynaptic autoreceptors: reduce transmitter release
Inhibition of […] and […] is important because they are used to transmit pain signal
Inhibition of Glu and Substance P is important because they are used to transmit pain signal
Biased Agonism
Receptor activated dictates which signal is activated
Opioids in CNS
Decreased body temp and blood pressure, pupils restricted, and increased blood CO2
Opioids in GI tract
Relief of diarrhea and dysentery acid
Opioids induce several behavioral effects
Analgesia:
- most effective pain-reliever
Changes in mood
- euphoria (MOR, DOR) - dysphoria (KOR)
Drowsiness
- sleep
Opioid PNS effects
- pinpoint pupils
- vomiting
- cough suppression (codeine)
- constipation
Death by opioid
- respiratory depression
- cardiac depression
Opioid overdose triad
Pinpoint pupil, unconsciousness, respiratory depression
- treat using Narcan
Acutely MOR agonist are […] and […]
Acutely MOR agonist are analgesic and reinforcing
- Analgesia
- Reward
Analgesia
Spinal- release endorphins that inhibit activation of spinal projection neurons
Supraspinal- above spinal cord
Reward
Increased DA release in NAcc
- B- endorphins are similar
- K-agonists: decreased DA
Analgesic properties of opioid are due to agonism of MOR located in brain and spinal cord
- Midbrain periaqueductal gray matter
- Locus coeruleus
- Raphe nuclei
- Dorsal horn of spinal cord
- anterolateral system- ascending pain information
Opioids regulate pain
- In spinal cord by small inhibitory interneurons
- Descending pathways originating in periaqueductal gray (PAG)
- At higher brain sites (emotional and hormonal aspects)
MOR agonists directly […] neurons and have reward properties
MOR agonists directly activate mesolimbic DA neurons and have reward properties
- ICSS
- Self-administration
- Microinjection studies
ICSS (intracranial self-stimulation)
opioids decreases the threshold current required for ICSS
- morphine or selective mu- agonist and place preference
Median forebrain bundle
Bar press rewards
Self-administration
IV use gradually increases over time
- similar to pattern seen in humans
Microinjection studies
Intra-VTA microinjection increases firing rate and DA release from VTA
Induces CPP and decreases threshold for ICSS
Opioids […], increases their firing rate, causing more DA release in N. Acc.
Opioids disinhibition VTA neurons, increases their firing rate, causing more DA release in N. Acc.
6-OHDA lesions […] self-administration, showing the rewarding properties of opioids also involve other, non-DA mechanisms
6-OHDA lesions reduce self-administration, showing the rewarding properties of opioids also involve other, non-DA mechanisms
Chronic opioid use produces increased craving, physical dependence and tolerance
- incentive sensitization
- pharmacodynamic tolerance
- withdrawal/ abstinence syndrome
Incentive sensitization
- increased invention salience
- craving; “wanting”
(Craving undergoes sensitization)
Pharmacodynamic Tolerance
- also metabolic and behavioral tolerance
- cross-tolerance with other OR agonists
Withdrawal/ abstinence syndrome
Loss of inhibitory opioid action at all receptors as blood levels of drug decline
*rebound hyperactivity
Cross- tolerance
Tolerance to one opioid drug—> other chemically related drugs also show reduced effectiveness
Detoxified
When abstinence signs end
Cross Dependence
Readministering any opioid will stop/ reduce withdrawal symptoms
Physical dependence occurs following long-term occupation of opioid
Acute action: withdrawal symptoms
Analgesia: pain and irritability
Respiratory depression: panting and yawning
Euphoria: dysphoria and depression
Relaxation and sleep: restlessness and insomnia
Tranquilization: fearfulness and hostility
Decreased blood pressure: increased blood pressure
Constipation: Diarrhea
Pupil constriction: pupil dilation
Hypothermia: hyperthermia
Drying of secretions: tearing, runny nose
Reduced sex drive: spontaneous ejaculation
Flushed and warm skin: chilliness and “gooseflesh”
Neuroadaptations underlie the transition to addiction
Nucleus accumbens
Locus Coeruleus
Periaqueductal Gray
Abrupt removal of opioid in tolerant/ dependent animals leads to a withdrawal syndrome
Normal
Begin morphine treatment: acute
Tolerance and dependence
Withdraw morphine (abstinence)
Withdrawal and normal
Neuroadaptations following chronic opioid use are related to […] and […]
Neuroadaptations following chronic opioid use are related to tolerance and withdrawal
Tolerance
- MOR desensitization: uncoupling of MOR and G protein occurs rapidly (min)
- MOR down-regulation and internalization occur more slowly (1-3 days)
Withdrawal (WD)
Intracerebral injection of naloxone to
- LC/ PAG - physiological symptoms of WD
- N. Acc.- aversive qualities of WD (depression, dysphoria)
Neuroadaptations following chronic opioid use are related to tolerance and withdrawal
Acute
Chronic
Induce WD
Acute Use
- activate MOR in LC
- Hyperpolarization; less AP firing
Chronic Use
- LC neurons gradually increase AP firing
- cAMP/ PKA activity gradually increases
- chronic morphine doesn’t change number of receptors (tolerance)
Induce WD
- administer naloxone to dependent animal
- LC neurons are over-excited
- cAMP/ PKA over-activated
Neurobiology of Opioid Addiction
Increased cAMP
PMOR
Increased LC
Increased DA release
POST NEUROADAPTATION;
MOR desensitization MOR internalization Tolerance LC hyperactivity Anti-reward
Positive feedback loop: LC to Central Nucleus of Amygdala and back
Innovative pain control
Dual- inhibition of peptidases
Dual MOR/NOR agonists
Dual-inhibition of peptidases
- inhibition of both ENK degrading enzymes
- fewer side-effects
- low abuse potential
Dual MOR/ NOR agonists
- potent, effective analgesia
- no respiratory depression or cardiac side effects
- no physical dependence, low abuse potential
2 components of pain
Early- immediate sensory component; signals onset of noxious stimuli and precise location
- Ad fibers - Spinothalamic tract —> posteroventrolateral (PVL) nucleus of thalamus —> primary and secondary somatosensory cortex
Late- strong emotional component (unpleasantness)
- C fibers
- Thalamus —> hypothalamus, amygdala, anterior cingulate cortex
Environmental cues have role in tolerance, drug abuse, and relapse
- Triggers- cues that act as secondary messengers
- Learning is critical in opioid use disorder
Detoxification is assisted using […] and […]
Detoxification is assisted using methadone and clonidine
- methadone maintenance program
Buphrenorphine (Buprenex) maintenance
Opioid partial agonist used to similarly to methadone
- High affinity, low Africans MOR
- Antagonist at KOR
Naltrexone (Trexan)
Commonly used narcotic antagonist
