Chapter 11: Opioids
Narcotic analgesics
Features
produce a sense of euphoria
create a sense of relaxation and sleep
high doses --> coma and death (because of respiratory infection; inhibits brain stem center that controls breathing reflex)
TYPES
opium: extract of poppy plant
opiate: substances derived from the poppy (i.e. morphine)
opioid: includes opiates, semi-synthetics (heroin), synthetics (fentanyl), and endogenous peptides (endorphins)
Heroin: first marketed by Bayer (1898) as a NONADDICTING substitute for codeine to control coughs
Levels of narcotics
Natural narcotics
opium
morphine
codeine
thebaine
Semisynthetic narcotics
From morphine
hydromorphone (dilaudid)
From thebaine
etorphine
Totally synthetic narcotics
pentazocine (Talwin)
meperidine (demerol)
FENTANYL
methadone (dolophine)
LAAM
Propoxyphene (Darvon)
Endogenous opioids
enkephalins
ENDORPHINS
dynorphins
endomorphines
heroin
oxycodone (percodan)
HEROIN STRUCTURE: 2 acetyl groups added to morphine
more lipid soluble (readily absorbed)
converted to morphine in brain
2-4x stronger than morphine when delivered IV
PO: heroin and morphine are equipotent
4 components of opioid intoxication (route of rapid admin-dependent (IV))
1) Rush: wave of euphoria within 10 seconds
2) High: general feeling of well-being (last for hours after rush)
3) Nod: overlaps with high, state of escape from reality
4) Being straight: no longer experiencing rush, high, or nod (NOT experiencing withdrawal yet)
withdrawal occurs 8 hours after taking the drug
reduce pain WITHOUT producing unconsciousness (not an anaesthetic)
Adverse effects of opioids
dysphoria, restlessness and anxiety, nausea and vomiting (affects the area postrema in the brainstem)
high doses, sedative effects --> unconsciousness
body temp and blood pressure fall, pupils become constricted (small pupils), respiratory failure
significant effects on GI tract: opioid induced constipation
Opioid Rectors and Endogenous Neuropeptides
Receptors
4 subtypes: m, S, K, NOP-R (distinct distributions in the brain and spinal cord --> mediates a wide variety of effects)
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
All opioid receptors are GPCRs
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
Endogenous opioids: neuropeptides
released by neurons at nerve terminal via Ca++ dependent exocytosis
not synthesized in the nerve terminals - they are PEPTIDES so they're synthesized in ribosomes
most synthesis occurs in rough ER
secretory granules in Golgi (filled with peptide) bud off and are transmitted to nerve terminal
Can be coexpressed with neurotransmitters
violates Dale's Principal that states only 1 NT per synaptic vesicle
4 precursor peptides are processed into smaller active opioids
Prodynorphin --> dynorphin
*Pro-opiomelanocortin (POMC) --> beta-endorphin
Proenkephalin --> enkephalin
Proniciceptin/orphanin FQ --> nociceptin
Opioids and neuronal inhibition
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
Opioids and Pain
opioids drug bind to opioid receptors and mimic the INHIBITORY action of endogenous opioids at MANY STAGES of pain transmission
Regulate pain in 3 ways
Within spinal cord
descending pathways from PAG
higher brain sites (cortical areas): influences the emotional and hormonal aspects of the pain response
inhibit the projection neuron (projection neuron carries pain signal to higher brain areas)
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)
Raphe: 5-HT neurons descend into spinal cord and inhibit firing of ascending pain projection signal
Reinforcement, Tolerance, Dependence
Reinforcement
Opioids are reinforcing
Mesolimbic DA pathway and opioid reinforcement
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
in animal studies, ACUTE pretreatment with opioids LOWER the threshold ICSS (enhances brain reward system)
Dependence
chronic opioid use --> physical dependence
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
Severity of withdrawal varies with specific drug and ROI
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)
Himmelsbach: Theoretical model of opioid tolerance and dependence
nervous system ADAPTS to disturbing presence of drug --> tolerance
If drug is withdrawn, the adaptive mechanism continues to function, causing rebound physiological effects (withdrawal symptoms)
Dealing with withdrawal: NE a2 autoreceptor
withdrawal activates NE system
symptoms
low energy, irritability, anxiety, agitation, insomnia
hot and cold sweats, goose flesh
abdominal cramping, nausea, vomiting, diarrhea
a2-agonists such as clonidine treat symptoms
Neuronal basis for tolerance/dependence: glutamate and NMDA receptor
tolerance to chronic morphine is reduced by non-competitive NMDA antagonist
increased opioid-induced PKC activation may phosphorylate NMDA receptor
enhances channel function
makes it easier to activate and contribute to tolerance via activation of nitric oxide synthase
Medication-Assisted treatment for opioid addiction
Methadone maintenance (PO): opioid agonist
little/no euphoria occurs PO
relieves craving
requires daily supervised admin
cross-dependence with heroin --> prevents severe withdrawal symptoms
normal euphoric effects of heroin are reduced, reducing likelihood of relapse
Cross tolerance becomes a PROBLEM when patients need analgesia in the ER
Buprenorphine: partial agonist
weaker effects than methadone and longer duration
doses are 1-3 times/week because effects are longer
Suboxone: buprenorphine + naloxone (opioid antagonist)
when taken PO, buprenorphine is absorbed but the naloxone is NOT
BUT, if crushed and injected, naloxone BLOCKS buprenorphine's euphoric effects
HEROIN ADDICTION TREATMENT (HAT)
supervised injectable heroin (SIH)
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
naltrexone: antagonist
longer duration of action than naloxone
effective when taken PO
few side effects
cravings are NOT eliminated
must detox first because naltrexone causes severe withdrawal symptoms
vivitrol: injectable, extended release naltrexone (given once a month)
Kratom: not FDA approved
substitute for opioid, reduces withdrawal symptoms
Acute opioid overdose: treat with naloxone (opioid antagonist)