Chapter 11 - Opiates

POPPY

An opium//from Afghanistan Elicits feeling of warmth and well-being followed by sleep. -eating/ smoking opium accepted in Islamic countries and replaced alc consumption (which was prohibited.) -1680: opium-based medicinal drink created. --> called "Laundanum" : treated teething pain and restlessness in infants, muscle aches and pain, and alcoholism.

Active ingredient in Opium = MORPHINE

First isolated in 1800s. (first time active ingredient of medicinal plant was isolated.) -extract: allowed doctors to prescribe it in KNOWN dosages. -in addition to morphine: codeine, thebaine, narcotine, etc. -structure of morphine discovered in 1925. -Differences in chem structure (codeine vs morphine) creates a drug that has less analgesic effect and fewer side effects than morphine (still good cough suppressant.)

4 Opioid Receptors

Mu --> highest affinity for morphine/ related. In brain and spinal cord. Account for role in analgesia and positive reinforcement, CV and R depression, and cough control nasuea and vomiting. Delta --> similar to Mu but more restricted. Found in forebrain structures. Accounts for role in olfaction, motor integration, reinforcement, and cog function. Kappa --> distinct distribution. K-receptor initially identified by high affinity binding to ketocyclazocine (opioid analog that produces hallucinations and dysphoria.) / in striatum and amygdala (BUT unique distrubtion in hypothalamus and pituitary. ) Accounts for pain perception, gut motility, dysphoria, water balance, feeding, temp control, and neuroendocrine function. NOP-R (recently added// but opioids dont bind to NOP-R ---> widely distributed in CNS and PNS. Accounts for role in analgesia, feeding, learning, motor function, neuroendocrine regulation. *each of these receptors: 370-400 amino acids/ G-proteins (metabotropic.)

Opioid Receptors and Endogenous Neuropeptides

Opioid drugs bind to specific neuronal receptors. --classic binding curve demonstrates that as the amount of radioactive opioids is increased, binding also increases and gradually tapers off until receptors fully occupied. ---leveling off of binding curve at B max shows a finite number of receptors exist. ---binding sites have high affinity for opioids ---binding shown to be reversible

Semisynthetic

This term refers to the fact that some narcotic drugs require chemical modifications of the natural opiates. LOOK AT 11.4

Prototypic partial agonist (Talwin)

analgesics// don't cause significant reps depression or constipation AND reduced risk for dependence.

heroin

created by adding 2 acetyl groups onto morphine molecule. (intended to be more effective in relieving pain without addiction.) *in actuality, morphine and heroin are almost identical (heroin converted to morphine in brain.) HEROIN is 2-4 x more potent when injected/ faster-acting bc change in molecule makes drug more lipid soluble and allows it to get to brain faster to act on receptors. When taken orally, they have similar effects.

Several families of naturally occurring opioid peptides bind to these receptors. Endomorphins --> Mu

endongenous neurochemical must exist to act on opioid receptors. First peptide: enkephalin (in the brain..)// number of peptides found to have similar properties: called endogenous opioids or ENDORPHINS. Furthermore: discovered that there were 4 propeptides (or large peptides) found that are broken into smaller active opioids: prodynorphin, POMC, proenkephalin, and orphanin FQ. <------------ manufactured in soma. Break down into peptide products, stored in vesicles, and transported down axon to be released at synapse. **each propeptides produce active opioid and non-opioid peptides. -Group of peptides w/ distribution in CNS: endomorphins --> bind to Mu. As potent as morphine in relieving pain.

4 principles types of opioid receptors

miu delta kappa NOP-R

Modifications to morphine's molecular structure...

produce partial agonists (drugs that bind readily but have less biological effect.) -when given w/ opioid that has higher effectiveness, they compete for the receptor and reduce action of more effective drug. can also produce pure antagonists (naloxone and nalorphine) --> have similar structure to opiates but no activity of their own. //can reverse opioid administration (bc they occupy opioid receptor sites.) ***IV administered naloxone can revive unconscious individ in seconds.. reverses opioid effects and saves lives.

Anesthetics

reduce sensations by depressing CNS

Opium and Cocaine

were not regulated in 19th century America. // 1914 --> Narcotics Act passed. // 1920s: limit prescriptions to medical use.

Opioids have most important effects on CNS and GI tract

-effects of opioids are dose and absorption-related *low-moderate doses: pain relieved, pupils constricted, respiration somewhat depressed. Partial impairment and drowsiness. Also cough suppressant/ actions on hypothalamus (leads to decreased appetite, drop in body temp, reduced sex drive, hormonal changes.) have actions in limbic system (relieve psychological pain or feelings.) -> can lead to increased use. *slightly higher dose: (IV or inhaled): elation or euphoria.. rapid penetration to brain needed. The "rush" isnt basis for abuse but is reinforcer for repeated use. / euphoric effect doesn't always accompany IV admin.(can have kind of neg effects too.. dysphoria, restlessness, anxiety, nausea. ---------> related to morphine's effect on area postrema (elicits vomiting)/ for the addict, this is a "good sick" bc conditioned w/ euphoria. *highest doses: sedative effects stronger --> unconsciousness. Body temp/ blood pressure fall. Pupils constricted. Respiration is very impaired (doesnt respond to high blood carbon dioxide levels by triggering increased respiration.)/ Respiratory failure is ultimate cause of death in overdose. *effects on GI tract: are greatest. / relief from diarrhea --> causes constipation (prevents life-threatening fluid loss associated w/ diarrhea that accompanise bacterial illnesses.) -------------> modified opioid molecules (loperimide.. cant cross BBB) slows GI function but doesnt effect CNS.

Bioavailability predicts physiological and behavioral effects

-morphine usually injected IM/ orally. // small fraction of the drug can cross BBB to act on opioid receptors. However uniform in rest of body and can cross placental barrier. -After metabolism in liver, most opioid metabolites are excreted in urine w/in 24 hours.

Opiates (how long have they been used?)

Since 1200 BC.// it was used for medical probs such as: headache, deafness, asthma, coughs, shortness of breath, colic, leprosy.

Localization

Propeptides found inb rain, spinal cord, P(autonomic)NS, areas related to pain and mood. POMC found in pituitary gland (releases hormones in response to hypothalamic releasing factors.) *hypothalamus releases CRF in response to stress (increases ACTH release from pituitary and glucocorticoids from adrenal cortex.) locations of peptides implicate them in pain suppression, reward, motor coordination, endocrine function, feeding, body temp, water regulation, response to stress. Peptides are co-localized w/ other NT in same neuron (acetylcholine, GABA, serotonin, catecholamines, and other peptides.) --> when peptides coexist w/ NT, modify function of NT. TABLE 11.1