drugs exam 2

Opioid-induced constipation

Affects anywhere from 40-80% of chronic opioid users Leads to significant gastrointestinal discomfort Can be quite debilitating Sometimes treated with brain-impenetrant mu receptor antagonists Current research aims to improve the side effect profiles of opioids by taking advantage of functional selectivity/biased agonism

Amphetamines - history

Amphetamine first synthesized in 1887 Was marketed as an asthma medication and decongestant in the early 1930s In the 1930s and 40s, amphetamines were thought to be useful for many disorders >>Tobacco smoking, head injury, radiation sickness, hypotension, hiccups, caffeine dependence, narcolepsy, hyperactivity Began to be abused in the late 1940s

Kappa opioid receptors

Bind to and mediate the effects of dynorphin Kappa agonists have significant analgesic effects, but they also induce dysphoria and some hallucinations For this reason, kappa agonists are not used clinically for the treatment of pain Kappa agonists are occasionally abused (e.g., salvinorin A from the salvia plant) Used for its hallucinogenic properties

Marijuana and monoamines

CB1 agonists increase cFOS immunoreactivity in dopaminergic neurons (Patel and Hillard, 2003) >>This reflects increased activity of DA neurons >>PBP = parabrachial pigmented nucleus of the VTA >>PN = paranigral nucleus of the VTA >>LC = locus coeruleus >>>Major norepinephrine-producing brain region >>CL = caudal linear nucleus of the dorsal raphe >>>Major serotonin-producing brain region In images - black dot means neuron has fired recently

CB receptors

CB1 and CB2 are G-Protein coupled receptors They are expressed at higher levels in the brain than most other GPCRs They signal through multiple pathways >>Classically thought to inhibit cAMP synthesis

CBD reduces pain sensitivity through TRPV1 channels

CBD is able to reduce pain when CB1 or CB2 are blocked

Morphine pharmacokinetics

Can be taken via numerous methods Smoked, injected, orally, rectally Subject to first pass metabolism (~50% of oral doses is metabolized prior to reaching the CNS) Half life is approximately 2 hours Self administration has to be monitored closely due to risk of overdose

Marijuana

Cannabis, pot, weed, wacky tobacky, ganja, herb, yerba, reefer Main active ingredient is tetrahydrocannabinol (THC) Has been used since the 3rd millennium BC >>Has been regulated/illegal since the start of the 20th century Leads to mild euphoria, changes in appetite, slightly hallucinogenic Can induce dry mouth, memory loss, cognitive impairments Its use is very controversial

Is Blue Dream really different from OG Kush?

Could differ in THC levels Cannabis sativa contains over 421 different chemical compounds, including over 60 cannabinoids Not all cannabinoids have identical pharmacology There are differences in potency/efficacy at CB1 and CB2 Some act on different receptors entirely TRPV1, TRPV2, TRPM8, and TRPA1 channels

Endocannabinoids

Endogenous cannabinoids Two major endocannabinoids have been identified: anandamide and 2-Arachidonoylglycerol (2-AG) The release of these compounds is thought to contribute to runner's high Levels of anandamide are typically held low by the activity of the enzyme fatty acid amide hydrolase (FAAH), which degrades anandamide >>Whether FAAH also degrades 2-AG is still somewhat controversial Because they 'compete' with cannabinoids for CB receptors, changes in the levels of endocannabinoids could influence marijuana sensitivity We produce endocannabiniods ourself - they contribute to runners high

Endogenous Opioids

Endorphins Enkephalins Dynorphins Endomorphins

Vaping allows for greater amounts of THC to be consumed

Evolab's formulas are standardized to contain 70% THC, 20% terpenes, and 10% other cannabinoids. Terpene and cannabinoid percentages in the strain-specific cartridges vary. Evolab Alchemy 500mg cartridges retail for $40 to $90. When you vaporize instead of smoking you don't get as many carcinogens as regular smoke

Mechanisms of reverse tolerance

Frequent marijuana use - causes lung damage but doesn't reduce capacity You're improving ability of dilatating lungs - exercise Can have lung function - still damages lung

Opioid-induced hyperalgesia

In response to chronic opioids, some individuals report an increased sensitivity to pain Previously non-noxious stimuli induce pain Underlying mechanism is not well known The incidence is not well established, but less than 25%

Freud and cocaine

Initially thought cocaine was a wonder-drug Could treat opioid addiction He considered it to have cured him of depression Later in life, he considered cocaine the third scourge of humanity after alcohol and heroin

Effects of chronic cocaine

Irritability, depression, paranoia Decreased appetite and weight loss Decreased libido Perforated septum Cocaine psychosis - hallucinations, anxiety and paranoia Sometimes perceive hallucinatory bugs crawling on the skin

Cocaine Pharmacokinetics - Absorption and Distribution

Only ~25% of snorted cocaine is absorbed into the blood IV injected cocaine is absorbed 100% Smoked crack cocaine can be absorbed better than snorted cocaine, but this is quite variable Cocaine is highly brain penetrant >>Concentration in the brain exceeds that in the plasma Cocaine readily crosses the placental barrier

Basis of Opioid Addiction

Opioids can directly activate neurons in the nucleus accumbens by binding to receptors in the Nac Opioids can also indirectly increase the activity of VTA neurons, thus leading to increased dopamine release

A G-protein-biased μ-OR agonist (TRV130)

Orange lines show G-protein signaling (cAMP accumulation) Black lines show beta-arrestin recruitment/signaling In A morphine's effect on two different signaling pathway Morphine is balanced agonist B is other drug that most activates G protein signaling

Derivative compounds made by modifying codeine or thebaine

Oxycodone (Percocet; slow release form is oxycontin) and hydrocodone (Vicodin

Pain

Pain indicates damage or potential damage to the body; tissue damage transduced by pain receptors. A-delta fibers: Quick, sharp pain C fibers: Long, dull pain

Timeline of drug development (and failure)

Phase 1: Single doses of TRV130 or placebo were delivered by infusion to 64 individuals. First time TRV130 was given to humans. Data presented in 2013 Phase 1b: 3 doses given to human volunteers, compared to morphine. Phase 2: Used in patients for bunionectomy and abdominoplasty patients. Compared to morphine. Phase 3: Was announced in Jan 2016. Will enroll 900 patients. FDA voted 8-7 AGAINST approval of TRV130 in October 2018 Did not outperform morphine with respect to efficacy Not sufficient evidence to state that its safety was superior to morphine's Some evidence of potential cardiac problems

What is pain?

Physical suffering or discomfort caused by illness or injury. Pain can occasionally occur in the absence of an identifiable injury Idiopathic pain, psychosomatic, psychogenic pain are terms that refer to pain for this the cause is unclear Fibromyalgia is a term that refers to a condition characterized by unexplained pain Psychosomatic > unknown cause in body Psychogenic > unknown cause in mind

Endorphins

Play a role in pain regulation Potentially also play a role in euphoria Some recent evidence that endorphins play a role in depersonalization

Blocking alpha 1 adrenergic receptors prevents the CP-induced increase in DA neuron activation

Praz = prazosin, an alpha 1 adrenergic receptor antagonist If you treat with a CB1 agonist it turns on dopamine neurons, but if you block adrenergic receptors This implies CB1 agonist is not direct CB1>adrenergic>dopamine

Mini-Summary

Preclinical evidence suggests that morphine works better when beta-arrestin 2 is not around (better therapeutic effects) Preclinical evidence suggests that morphine has fewer side effects when beta arrestin 2 is not around Hypothesis: Maybe a drug that only activates G-protein signaling downstream of mu opioid receptors (not beta arrestin) would be more effective and have fewer side effects than morphine

Delta opioid receptors

Primarily mediate the effects of enkephalins Are expressed primarily in the basal ganglia and neocortex (involved in sight and hearing, complex thought, motor planning) Thought to play a role in mood regulations Do induce analgesia Some argue that delta opioid receptors are selectively involved in chronic pain whereas the mu opioid receptor modulates acute pain Still somewhat controversial

Conditioned Place Preference - a preclinical test of rewarding properties of drugs

Side depends on which side you put cocaine on

Cannabinoid effects on neurotransmitter systems

The acute stimulation of CB1 receptors increases the activity (spontaneous firing rate) of noradrenergic (NE), serotonergic (5-HT) and dopaminergic (DA) neurons The chronic stimulation of CB1 receptors has also been reported to increase the firing rates of NE, 5-HT and DA neurons >>Little tolerance has been reported

Crack babies

What do we know, or what do we think we know, about 'crack babies'? Congenital anomalies have been reported to occur in up to 40% of infants exposed to cocaine in utero >>Congenital = occurring from the time of birth, not necessarily genetic Decreased head circumference and decreased birth weight Withdrawal symptoms are common in babies born to addicted mothers Prenatal and post-natal care are often impaired Other drug use is common in mothers

Oral Administration

When eaten, the onset of marijuana action typically occurs in 30-60 minutes >>Peak effects occur 2-3 hours after ingestion THC is ~3 times more effective when smoked compared to when taken orally

Opioids vs. Medical Marijuana

While marijuana is not without negative side effects, most would agree that opioid side effects and abuse potential are worse than those for opioids In some cases, marijuana could be used as an alternative for opioids or could be used in conjunction with opioids to allow for lower doses of opioids Both marijuana and opioids are most commonly prescribed to treat pain Marijuana is also prescribed for seizures, glaucoma, pain associated with multiple sclerosis, muscle spasms, nausea associated with chemotherapy

Sites of Opioid Action

While there is some specificity there is a lot of overlap

Losing β-arrestin2 leads to increased morphine analgesia in mice

Wild type mouse experience analgesic response to morphine Beta arrestin 2 knockout mice have longer more lasting response to morphine Beta knockout are benefitting more than wild mice

Can safer/more effective opioids be developed?

Would need to increase the therapeutic index Biased agonists might be desirable, if the signaling pathways leading to therapeutic and side effects are distinct

Medical Marijuana

"legal" in 33 states and in DC Still very controversial The results of a meta-analysis by Hill, published in the Journal of the American Medical Association (2015), concluded that there is high quality evidence in favor of using marijuana for conditions of chronic pain and for multiple sclerosis, but not for anything else BUT, relatively little research has been done given the legal status of marijuana

Behavioral Tests relevant to Opioids

1. Count fecal boli More poops = less constipation 2. Glass Bead Assay Surgically implant glass bead 2 cm into the colon See how far it goes or see how long it takes to get expelled >>These two measure opioid side effects 3. Hot plate assay Place a mouse or a rat on a hot plate Measure the amount of time for it to lick its paw Longer time before licking = less pain >> Measure analgesic effect of opioids

Crack babies 2

2 It has been relatively difficult to get study samples of individuals who were exposed to cocaine in utero, but not to other drugs (alcohol and nicotine) When alcohol and nicotine exposure are controlled for, most of the effects of cocaine in utero (other than withdrawal) are relatively mild Still difficult to determine which effects are the result of cocaine vs. poor diet, parenting, early life stress, poverty, et cet. TAKE HOME: crack is still wack, but some of its consequences for children have been overstated

Excretion of Marijuana

11-hydroxyl-delta-9-THC is then converted to an inactive metabolite (11-nor-9-carboxy-delta-9THC or THC-COOH) THC-COOH is what is excreted in the urine The half life of THC-COOH in urine is 13 days The standard cutoff threshold for a positive/failed drug test is 50 ng/ml

Acute Physiological/Psychological effects of Cocaine

A burst of energy - a rush, or a high If injected or smoked, the high hits within seconds and lasts 5-10 min If snorted, the effect is less intense but lasts 15-30 min A general sense of well-being, good mood, confidence Possibly an aphrodisiac, but somewhat controversial Excite the sympathetic nervous system, inhibit the parasympathetic nervous system Overdoses can lead to seizures

Cocaine and neurotransmitter systems

According to your book (and most textbooks), "cocaine blocks the reuptake of all the monoamine neurotransmitters, although most of its effects appear to be due to the blockade of dopamine reuptake." This is likely true, but it is also likely an oversimplification.

Pharmacologic control of pain

Anti-pain medications can target: Pain receptors in the periphery >>Topical anesthetics Peripheral sensory neurons Spinal cord ascending pain pathways Descending pain pathways in spinal cord Brain centers associated with pain sensation Different drugs can affect one or several or even all of these processes

Opioid Abuse - by the numbers... as of 2011

Approximately 281,000 American over the age of 12 had reported using heroin in the past month (some recent estimates are higher) Approximately 434,000 Americans had used OxyContin for nonmedical purposes Individuals may become addicted to heroin after not being able to use oxycontin >>heroin is cheaper and more readily available

Effects of Cocaine on Neurotransmitter Levels

Arrow when cocaine is administered Serotonin has highest increase in response to cocaine All 3 NT crazy increase in response to cocaine Citalopram is SSRI

TRV130 induces less respiratory depression than morphine

B causes respiratory depression Better separation between good effect and bad effect of bias compound (TRV)

Acute toxicities

Chart with ratios of fatal does to effective dose You would need to have more than a thousand times an effective dose of marijuana for it be lethal Alcohol only 10 times more

Cocaine and alcohol

Cocaethylene is more euphoric than cocaine Frequently taken together Vin Mariani was one popular early example of cocaine+wine The makers of coca-cola originally had mixed cocaine with alcohol, but when alcohol was outlawed in Atlanta, they replaced it with syrup to make coca-cola Vin Mariani had ~6-8 mg per fluid ounce, so a 5 oz glass of wine would give ~30-40 mg. For comparison, a "line" of coke that someone might snort can range from 40-200 mg. Having it pass through the digestive track would greatly diminish potency though.

Cocaine Pharmacodynamics

Cocaine blocks the dopamine transporter >>Leads to increased levels of extracellular dopamine It also inhibits the serotonin transporter and the norepinephrine transporter >>Raises the levels of 5HT and NE >>The relative importance of each of these pharmacological targets remains somewhat debated Chronic cocaine leads to a 20% reduction in DA receptor expression >>Can last up to 4 months post cocaine >>Can interfere with natural reward processing

Cocaine Pharmacokinetics - Elimination

Cocaine has a biological half-life of 30-90 minutes Metabolized by enzymes in the liver and brain The major metabolite of cocaine (benzoylecgonine) can be detected in urine for 48 hours in one-time users, up to several weeks in chronic users When cocaine and alcohol are taken together, this affects cocaine metabolism and forms cocaethylene, which is pharmacologically active and more toxic than cocaine >> cocaethylene can increase experience of cocaine but is also more toxic than just cocaine

Cocaine - summary

Cocaine is a highly addictive substance taken via multiple administration routes It has numerous negative health consequences Cocaine affects multiple neurotransmitter systems, although its effects on dopamine are most widely noted

Cocaine Purity

Cocaine is frequently 'cut' with inactive substances or other impurities Baking soda, flour, amphetamines are commonly used to cut cocaine As much as 70% of cocaine in the US is contaminated with levamisole, a drug that is known to lead to skin necrosis

Street names for cocaine

Coke. Flake. Snow. Blow. White. Toot. Llello (Spanish), sometimes spelled yeyo Bump Line Rail

The effects of genetic loss of NET

If you lose NET mice end up being super sensitive to cocaine

CBD is now FDA-approved!

In Jan. 2018, the FDA approved CBD for use in seizure patients (under the brand name Epidiolex) Estimates are that it could cost ~$32,500 a year In states where medical marijuana is 'legal', the equivalent amount of CBD oil would cost ~$3,800

Opioids act to alleviate pain both centrally and peripherally

Diagram in ppt

Cannabinoids could affect pain sensation through any of these mechanisms via:

Direct effects Directly regulating ion channels/receptors that play a role in pain sensation Indirect effects Through influences on endogenous opioid signaling for example

Opioids

Drugs derived from or related to compounds isolated from the opium poppy. >>NOT from the yellow California poppy or the red Oriental poppy Drugs are typically used to treat pain >>But they are also frequently abused Act by activating specific receptors in the brain that are sensitive to opioids >>Analogous to how the brain has cannabinoid receptors for endogenous cannabinoids, the brain has opioid receptors for endogenous

Psychostimulants

Drugs that evoke alerting, arousing or behavior-activating responses Cocaine, amphetamine, methamphetamine, ecstasy, caffeine The effects of these drugs are not identical BUT... most people (and animals) cannot discriminate between the effects of cocaine vs those of amphetamine Augment signaling through several neurotransmitter systems Primarily via the regulation of neurotransmitter transporters

Mechanisms of THC-induced analgesia

Dynorphin A, an endogenous opioid, is required for THC to enhance morphine analgesia This supports an indirect effect of THC (via endorphin release) THC isn't binding to opioid receptor or making morphine better >>it is causing another endorphins to be released that can bind to different opioid receptors

Functional Selectivity at μORs?

Genetic loss of β-arrestin2 prevents morphine-induced constipation in mice and reduces morphine-induced respiratory depression Wild type mice have more respiratory depression than knockout Knockout feel less pain and are able to breathe easier Wild type mice are more constipated

Long-term effects of marijuana use

Graph in ppt Followed ~3000 twins from age ~9-12 until age ~20 Effects were not huge, but trend was for marijuana users to display lower intelligence scores Only ~37 and 50% of the USER groups had smoked marijuana over 30 times in the study period Only ~20-22% of the USER groups were daily smokers

Urine testing - regular use

Graph in ppt Regular users have much longer duration You can have positive drug tests at least a month after use - if use is regular

Derivative compounds made by modifying morphine

Heroin (diacetylmorphine), hydromorphone (Dilaudid) and oxymorphone (Opana)

DAT-KO mice still self-administer cocaine

How much mice will self administer cocaine Wild type - when able they will give themselves cocaine w/o dopamine transporter - will still inject themselves with cocaine over and over

More Heroin Pharmacokinetics

If taken orally, heroin is subject to extensive first-pass metabolism Also, it is rapidly de-acetylated Which converts it to morphine Taking a heroin pill would not be much different from taking a morphine pill Injecting heroin bypasses the first-pass metabolism and prevents most de-acetylation Heroin's elimination half-life is 2-6 minutes!

Endomorphins

Lead to analgesia Act primarily through mu opioid receptors Some evidence that endomorphins have fewer side effects (respiratory depression) than morphine itself

Forms of cocaine

Leaves of the coca plant are ~1% cocaine Leaves are soaked and mashed to make coca paste (60-80% cocaine) Coca paste is then treated with hydrochloric acid to make cocaine hydrochloride, which is a water-soluble powder Cocaine base (freebase, crack) is insoluble in water, but it can be vaporized/smoked Can convert Cocaine-HCl to freebase or crack and back

Treatment with THC increases the potency of morphine

Leftward shift in dose response curve when THC is with morphine

Loss of either DAT or SERT (5HTT) does not prevent cocaine-induced CPP

Low dose - will prefer cocaine side Without dopamine transporter or serotonin transporter - mice still have happy times with cocaine

Summary

Marijuana is technically one of the safest drugs available from an acute lethality standpoint BUT... it does lead to cognitive problems AND, just like smoking anything, it has the potential to lead to long-term respiratory problems and possibly cancer Its therapeutic effects (other than for pain) are not well established The FDA won't permit/authorize most studies...

Purely synthetic compounds

Methadone, meperidine (Demerol), tramadol (Ultram) and buprenorphine (Suboxone)

Loss of both DAT AND SERT blocks cocaine-induced CPP

Mice with neither DAT and SERT now dopamine cant give reward response

Summary

Millions of Americans live with daily pain or experience injuries/conditions that lead to severe pain over an extended period Existing medications are very addictive, have many negative side effects Given the current controversies surrounding opioid use, the FDA is rightfully concerned about introducing new opioids and wants overwhelming evidence that any new opioids are safer/more effective than existing treatments before approving them

Marijuana Statistics

More than 97.5 million Americans over the age of 12 have used illicit marijuana Often considered to be a benign recreational drug. As many as 1 in 10 users becomes dependent >>Typically thought to be more of a psychological dependency than a physical dependency

Morphine vs Heroin Pharmacokinetics

Morphine - crosses the blood-brain barrier more slowly; less addictive/euphoric Heroin - crosses the blood-brain barrier more rapidly; more addictive/euphoric

TRV appears to have a better therapeutic index than morphine

Morphine not good therapeutic index A B TRV has better therapeutic index

Natural Compounds directly extracted from opium

Morphine, codeine, thebaine

Opioid pharmacodynamics

Morphine, heroin, oxycontin, fentanyl share relatively similar pharmacodynamics profiles in that they activate mu receptors There is more variability with respect to effects on kappa and delta receptors Fentanyl is highly potent (50-100 times more than morphine) Relatively high therapeutic index, but the extreme potency makes this drug still dangerous Important functional differences frequently result from pharmacokinetic effects

Pharmacodynamics of Marijuana

Most cannabinoids activate two different G-protein coupled receptors >>Cannabinoid receptor 1 (CB1) - expressed in the brain >>CB2 - classically thought to be expressed primarily in the periphery, but recent evidence that it is also present in the brain Can indirectly influence dopamine signaling >>Less addictive than agents that directly affect DA

Marijuana Pharmacokinetics - Absorption

Most marijuana has a THC content of 5-10% >>But this number has been trending upward with the slightly changing legality of marijuana If a person smokes one gram of marijuana (5% THC), 50 mg of THC would be present in the joint >>25-50% of this is available in the smoke (12-25 mg) >>Of this, anywhere from 1-10 mg is absorbed into the bloodstream Peak blood levels of THC occur about 10 min after smoking >>In the above example, the peak blood level would probably be ~200 ng/ml >>Some people can detect feeling 'high' with as low of a blood level as 5 ng/ml

Three Major Subtypes of Opioid Receptors

Mu opioid receptors Delta opioid receptors Kappa opioid receptors All are G-protein coupled receptors and they preferentially respond to different endogenous opioids They differ in the neurons/brain areas in which they are expressed, which contributes to their distinct functions You may also hear about nociceptin receptors Nociceptin receptors are structurally related to other opioid receptors, but they do not bind to opioids They bind to nociceptin (which is similar to dynorphin A)

Four Major Categories of Opioids

Natural Compounds directly extracted from opium Derivative compounds made by modifying morphine Derivative compounds made by modifying codeine or thebaine Purely synthetic compounds

Cocaine

Obtained from the coca plant Earliest use was by chewing coca leaves Today, 90% of Peruvian men in the Andean highlands chew coca leaves In the US, cocaine consumption usually occurs via snorting 'lines' of cocaine or smoking crack cocaine

Marijuana 2

Roughly half of Americans have tried marijuana About 1 in 8 has used it within the past year THC has very low toxicity, but when smoked, other components of smoke can have adverse effects (basically the same as smoking cigarettes) >>Ingesting smoke is bad for you no matter what it is Over 2.1 million Americans are currently taking medical marijuana Very unique pharmacology >>Leads to some excitatory effects and some inhibitory effects on neurons

Transporters

SERT = serotonin transporter (also 5HTT) DAT = dopamine transporter NET = norepinephrine transporter >> transport neurotransmitters from synapse (or other extracellular space) into the cytoplasm VMAT = vesicular monoamine transporter >>Transports dopamine, serotonin, norepinephrine, epinephrine, and histamine into vesicles; already in presynaptic neuron

Amphetamine street names

Speed Mollies (black or blue) Uppers Dexies Poppers

Cognitive consequences of cannabis use

Studies consistently report significant cognitive impairment in response to marijuana. Comparing heavy smokers (>5000 times) to light smokers (<50 times): Heavy smokers had worse word recall at 0, 1 and 7 days of abstinence No differences between the groups at 28 days of abstinence Pope et al., 2002 Some studies do find long-term effects Effects are most severe during incite intoxication

Medical Marijuana and Opioids

Studies have shown that: Cannabis use is associated with 64% lower opioid use in patients with chronic pain. Cannabis use is associated with better quality of life in patients with chronic pain compared to opioid use Cannabis use is associated with fewer medication side effects and medications used compared to opioid use. While there is potential for dependence, it is less than that observed with opioids

THC metabolism

THC is metabolized by hepatic cytochrome P450 enzymes into an active metabolite (11-hydroxy-delta-9-THC) THC elimination is slow, a half-life of ~30 hours Thus, it can stay in the body for days to weeks This allows for 'reverse tolerance' - if someone smokes frequently, the doses can be additive

THC distribution

THC readily crosses the blood-brain barrier THC readily crosses the placental barrier THC is distributed throughout the body, especially in areas with high concentrations of fatty material

Transient Receptor Potential Cation Channels (TRP channels)

TRPV1 is a receptor that provides sensations of heat and pain TRPV1 is the capsaicin receptor >>Capsaicin is what makes chili peppers hot TRPA1 is a sensor for environmental irritants giving rise to somatosensory modalities such as pain, cold and itch Allyl isothiocyanate is in wasabi >>Activates TRPA1 and TRPV1

Profile of a cocaine user

Tend to be young males Often addicted to multiple drugs 1/3 have anxiety disorders, 2/3 have depression Approximately half of cocaine addicts are alcoholics Many who inject cocaine do so in combination with heroin speedball

Mu opioid receptors

There are mu1, mu2, and mu3 receptors Are present both pre- and post-synaptically Expressed in the periaqueductal gray (and other brain regions) and the spinal cord Also expressed in the intestine Mu agonists can cause severe constipation

Relative safety of marijuana

There are very few CB receptors in the brain stem, thus marijuana does not affect most basic bodily functions, like respiration THC is a partial agonist, with fairly low efficacy >>Less efficacious than the endogenous CB ligand, anandamide >>when endocannabinoid levels are low, would serve to enhance cannabinoid signaling >>when endocannabinoid levels are high, would inhibit endogenous cannabinoid signaling THC and CBD can't kill you - there's no receptors on pons and medulla

Cannabinoids inhibit the effects of capsaicin

They induce desensitization of TRPV1/TRPA1 channels This likely accounts for their 'paradoxical analgesia effects' All cannabinoids lead to reductions in how effect capsaicin is

Enkephalins

Thought to play a role in nociception, but still debated some evidence for a role in amphetamine responses Primarily act through delta receptors

Dynorphins

Thought to play a role in nociception, some evidence for a role in cocaine responses and depression and stress responses Increase appetite (via hypothalamic effects) Primarily act through kappa receptors

Cocaine tolerance

Tolerance develops to the euphoric effects of cocaine Sensitization occurs to the motor and brain excitation effects of cocaine >>This can lead to an increased risk of seizures >>"Kindling effect" - heightened sensitivity to repeated administration of the same drug. The opposite of tolerance People are less able to achieve euphoric effects as they take more cocaine Need more cocaine over time for positive effects Need less and less cocaine over time to increased risk of seizures

Acute heroin vs heroin withdrawal

chart in ppt