Psychopharm Quiz 6 - Nicotine and Caffeine

Derivatives from opium

codeine, thebaine, morphine

semi-synth derivatives of morphine

heroin, dilaudid

semi-synth derivatives of thebaine

buprenex, oxycodon

krokodil

cheap knock-off of heroin that originated in Russia, extremely dangerous, crocodile-like skin

synthetic narcotics

methadone, fentanyl

narcotic routes of admin

oral, nasal, injection

morphine routes of admin

intra-muscular injection, IV, oral

opium routes of injection

smoking

heroin routes of admin

snorting (rapid absorption), skin popping (subcutaneous injection), mainlining (injection)

heroin has low bioavailability if taken

orally due to first pass; snorting/injection rapid

heroin is 10x more lipid soluble than

morphine, and readily passes the BBB

heroin is broken down in the liver into

morphine & morphine-6-glucoronide; excreted in urine

morphine absorption

low oral bioavailability (25%)

morphine crosses into the brain

slower than heroin

morphine's active metabolite is

morphine-6-glucuronide; excreted in urine

Fentanyl absorption

Injection, transdermal patch, oral, intra nasal

fentanyl has the highest bioavailability following

injection, intra nasal & transdermal patch, lowest with oral

fentanyl is 100x more potent than

morphine and is highly lipid soluble

fentanyl distribution

Rapid, widespread distribution to lungs, heart, kidneys, brain, liver, muscles

fentanyl is broken down in the liver into

inactive norfentanyl; excreted in urine

molecular structure of morphine and its derivatives indicated

probable structural features of opioid receptors

Naloxone's blocking effects can be overcome by

increasing concentrations of morphine, showing competition for the receptor

Not long after opioid receptors were identified,

the natural neuropeptide ligands that act at the receptors were characterized

narcotic receptor subtypes

mu, kappa, delta

mu-receptors

have a high affinity for morphine; have wide distribution in the brain and spinal cord

delta-receptors

predominantly found in forebrain structures; consistent with roles in modulating olfaction, motor integration, reinforcement, and cognitive function

kappa-receptors

found in the striatum and amygdala, hypothalamus and pituitary; may participate in regulation of pain perception, gut motility, and dysphoria

heroin, morphine, and methadone are

agonists

buprenex is a

partial agonist

naltrexone and narcan are

antagonists

endogenous opioids include

endorphins, enkephalins, dynorphins

Endogenous opioids (endorphins) plus non-opioid peptides are formed from

larger propeptides (precursor peptides)

precursor peptides include

prodynorphin, POMC, proenkephalin, Pronociceptin/orphanin FQ

propeptides are concentrated in areas

related to pain modulation and mood

POMC is concentrated in

the pituitary gland

CRF is released from the hypothalamus in response to

stress; increases ACTH release from the pituitary and ultimately glucocorticoids from the adrenal cortex

CRF also causes rapid increase in

POMC mRNA and subsequent increase in release of β-endorphin from the pituitary

many types of stressors increase both

CRF and POMC, suggesting a link between pain and stress regulation

opioids and N/OFQ work through

G proteins and second messengers to reduce synaptic transmission

Opioids and N/OFQ postsynpatic inhibition

opens potassium channels - hyperpolarization

Opioids and N/OFQ axoaxonic inhibition

closes calcium channels - decreases amount of transmitter released

Opioids and N/OFQ presynaptic autoreceptors

reduce release of a co-localized transmitter

opioids and N/OFQ inhibit

adenylyl cyclase

two components of pain

first (early) and second (later)

first/early pain

immediate sensory component, signal carried by myelinated A-delta neurons

A-delta neurons conduct action potentials

rapidly; transmitted from spinal cord via spinothalamic tract to PVL nucleus of the thalamus, then the somatosensory cortex

second/later pain

emotional component; signal carried by thin, unmyelinated C fibers

second pain has a slower

transmission; goes to the thalamus, but gives off collaterals to several limbic structures and the anterior cingulate cortex

Location and time course of pain-evoked neural activity in humans is studied using

MEG

first pain was temporally related to activation of

the primary somatosensory cortex

second pain was strongly associated with

anterior cingulate activation

both types of pain were associated with activity in

the secondary somatosensory cortex

opioid drugs mimic

the inhibitory action of endogenous opioids

Opioids reduce transmission of pain signals at the spinal cord in two ways:

spinal interneurons and the descending pathway

inhibitory spinal interneurons release

endorphins that inhibit activation of spinal projection neurons

descending modulatory pathway

inhibit projection neuron or excitatory interneuron, or excite inhibitory opioid neuron; most important pathway originates in the PAG in the midbrain

the body has two pain pathways

ascending and descending

ascending pathway

transmits pain signals to the brain; tells us we're hurt

descending pathway

shuts down the ascending pathway; stops pain

opioids inhibit which pathway?

the ascending pathway, and disinhibit the descending pathway

binding of opiates to opioid receptors blocks

the transmission of pain signals in the spinal cord

opioid activity also occurs in the supraspinal locations, including

sensory areas, limbic structures, and hypothalamus; may be responsible for the emotional component of pain

PET imaging showed significant negative correlation between

mu-opioid activity in the NAcc, amygdala, and thalamus and reported sensory pain scores

Membrane protein crystallization technology has determined the crystal structure of

all four opioid receptor types

Understanding the details of receptor structure and ligand-receptor binding will result in

structure based drug design

PZM21 was found to act on the

mu-opioid receptor and had analgesic effects in mice. Effects lasted longer than morphine with fewer side effects

beta endorphin and opioid drugs increase

VTA cell firing by inhibiting GABA cells

the inhibition of GABA cells leads to

increased firing and greater DA release in the NAcc

dynorphin acts on what receptors?

kappa receptors on DA neuron terminals, and can reduce release

chronic use of opioids can lead to neuroadaptive changes, which are responsible

for tolerance, sensitization, and dependence

cross-tolerance among opioids can occur

After chronic heroin use, codeine will elicit a milder-than-normal response even if the individual has never used codeine before

craving or desire for the drug undergoes

sensitization, but the neural mechanism responsible for the high, or liking of the drug, remains unchanged or decreases as tolerance develops

the most significant factor of the opioid epidemic

misleading and aggressive marketing of OxyContin to doctors and patients by the maker, Perdue Pharma

OxyContin became a popular street drug

and abuse and overdoses spread around the country

heroin and counterfeit pills are now being adulterated with illicitly manufactured

fentanyl, 50 times more potent than heroin

environmental cues can be classically conditioned to

drug taking

after repeated drug admin in the same environment

animals show physiological signs of anticipation in that environment

Euphoria may be associated with camaraderie of the drug-using subculture, drug acquisition activities and drug injection rituals, which become

secondary reinforcers and act as triggers that promote drug taking

a drug addict may find that tolerance is reduced in

a new environment, which may contribute to overdosing

tolerance occurs rapidly with opioids

With overdose, patients often succumb to respiratory failure

Medullary tolerance takes longer to develop than other euphoric effects, but

opioid-tolerant patients do not develop complete tolerance to medullary processes; susceptible to death

What are the opiate user's desired effects?

pain management, sedation, euphoria

symptoms of opiate intoxication

miosis, nodding, hypotension, euphoria, bradycardia, depressed respiration

miosis

small pupils; except with Demerol use which causes paralysis of the ciliary body and pupils dilate

acute opiate effects

Euphoria, drowsiness, body warmth, heavy feeling in limbs, decreased sexual desire, impaired social interactions

physiological effects of opiates

Respiratory depression, lowered core body temperature, flushed skin, itching, pupillary constriction

long-term opiate effects

Impotence, constipation, hypoxia, collapsed veins, decreased immune function

Changes in brain activity have been recorded by PET scans in

drug users exposed to drug cues that increase their craving

during craving, blood flow is increased in

the amygdala and anterior cingulate (similar to cocaine), suggests importance of emotional memory and expectation.

opioids in general depress

CNS function; opioid withdrawal is rebound hyperactivity

Abstinence signs reflect a loss of

inhibitory opioid action at all receptors in the CNS and elsewhere, as blood levels of the drug gradually decline

opiate withdrawal timeline

6-12 hours for short-acting, 30 hours for long-acting

opiate withdrawal symptoms peak around

72 hours

early opiate withdrawal symptoms

Flu-like symptoms, runny nose, tearing, sweating, yawning, insomnia, tremors in hands and legs

late opiate withdrawal symptoms

Elevated HR & BP, nausea, vomiting, diarrhea, joint & muscle pain/twitching, restlessness/anxiety, spontaneous orgasms/ erections

there is a high relapse rate with

narcotics

rapid detoxification is the most effective treatment for narcotic addiction

in-patient treatment; briefly anesthetized and treated with Naltrexone (antagonist)

narcotic withdrawal can be combatted with other drugs

methadone, suboxone, naltrexone

methadone is a full agonist with

lesser high than other narcotics, allows addicts to avoid uncomfortable withdrawal symptoms & prevents craving

suboxone