Opioid Receptors & Effects PDF

Mu (μ) receptors Main target of opiates like morphine and heroin. Responsible for pain relief, feelings of euphoria, and sedation. Can also cause side effects like respiratory depression and dependence. Kappa (κ) receptors Contribute to pain relief, but their effects are l...

Mu (μ) receptors Main target of opiates like morphine and heroin. Responsible for pain relief, feelings of euphoria, and sedation. Can also cause side effects like respiratory depression and dependence. Kappa (κ) receptors Contribute to pain relief, but their effects are less intense than mu receptors. Can cause feelings of dysphoria (unease or discomfort) rather than euphoria. Associated with some hallucinatory effects in certain drugs. Delta (δ) receptors Play a role in modulating pain and enhancing mood. May contribute to reducing anxiety or depression, but less studied than mu or kappa. Sigma (σ) receptors Originally thought to be part of the opioid system but are now considered non-opioid. Associated with psychedelic effects and responses to some drugs like PCP Opioids: Metabolization Key Points: ​ General Overview: 1. Many opioids are inactive until metabolized into their active forms in the liver. 2. Metabolization is rapid, except for some synthetic opioids with extended durations. ​ Metabolization of Key Opioids: 1. Heroin: Rapidly metabolized into morphine (active form). Half-life: ~30 minutes. 2. Codeine: Metabolized into morphine and other active metabolites. Primary enzyme: CYP2D6. 3. Methadone: Slow metabolism; prolonged effects. Half-life: 10–25 hours. Metabolism: Primarily metabolized by the liver through CYP3A4 and CYP2B6 enzymes. Metabolites: Methadone is not converted into any active metabolites. Its pharmacological effects are primarily due to methadone itself,  which has a long half-life (10–25 hours), making it suitable for managing opioid dependence 4. LAAM (Levo-alpha-acetylmethadol): Metabolized into active metabolites with long-lasting effects. Half-life: 36–48 hours. 5. Fentanyl: Rapid metabolism in the liver. Half-life: 1–2 hours Metabolism: Fentanyl is metabolized by CYP3A4 enzymes in the liver. Metabolites: Fentanyl is metabolized into inactive metabolites, which are then excreted primarily in the urine. Main Action: The analgesic effects of fentanyl are due to the parent drug, and it does not have active metabolites that contribute significantly to its effects Opioids: CNS Effects: Key Points: Analgesic Effects: ○ Mechanism: Opioids act at Mu, Delta, and Kappa receptors in the spinal cord to block incoming pain signals. Opioids also increase activity in the periaqueductal gray area (PAG), which sends signals to the raphe nuclei. Serotonin Release: The PAG stimulates the raphe nuclei, leading to the release of serotonin at interneurons in the spinal cord. Inhibition of Pain Signals: The serotonin release triggers the release of enkephalins or dynorphins which bind to opioid receptors on pain-signaling axons and inhibit the release of substance P, thus blocking pain transmission. ○ Emotional Regulation of Pain: Opioids reduce the aversive emotional experience of pain, mediated by opioid receptors in the limbic system and frontal lobe. ​ CNS Depression: ​ ○ Respiratory Depression: Opioids depress the respiratory center in the brainstem, leading to slower breathing rates, which is a primary concern in overdose. ​ ○ Cough Suppression: Opioids also suppress the cough center, making them effective in treating coughing but also contributing to respiratory depression.  ​ ○ Vomiting Center Depression: Initially, opioids have excitatory effects that can lead to nausea and vomiting, which is why they are often given with anti-nausea agents (e.g., graval). ​ Other CNS Effects: ​ ○ Drowsiness: Opioids cause sedation, leading to drowsiness. ​ ○ Sex Hormone Suppression: Opioids decrease sex hormone levels, leading to reduced libido in both sexes, amenorrhea (stopped menstruation) in women, and atrophy of secondary sexual characteristics in men Opioids: Effects on the Body: Key Points: Eye Effects: ○ Pupillary Constriction (Miosis): Opioids cause constriction of the pupils, a characteristic effect called miosis. Mechanism: The exact mechanism is not fully understood, but it is believed to involve opioid receptors in the brainstem affecting the parasympathetic nervous system. Gastrointestinal Effects: ○ Reduced Peristalsis: Opioids diminish peristalsis in the intestines, leading to slower movement of material through the digestive tract. Decreased Muscle Tone: Opioids decrease muscle tone in the intestinal walls, further slowing down digestion. ○ Constipation: The combined effects of reduced peristalsis and muscle tone result in constipation. Fecal Dehydration: Slower movement through the intestines leads to increased water absorption, causing fecal dehydration, which contributes to constipation. Opioids: Psychological Effects: Key Points: 1. Euphoria: ○ Mechanism: Mediated by Delta receptors. Indirect activation of dopaminergic neurons projecting to the nucleus accumbens, which is involved in the brain’s reward pathway.  ○ Effect: This leads to the feeling of intense euphoria, commonly experienced with opioid use. 2. Dysphoria: ○ Occurrence: First-time use may result in dysphoria (unpleasant feelings). For some individuals, dysphoria can be chronic with certain opioids. ○ Mechanism: Mediated by Sigma receptors, which are implicated in negative emotional responses. 3. Decreased Concentration: ○ Effect: Opioids cause decreased concentration and cognitive impairments, likely due to their sedative effects. This is partly because opioids induce sleepiness, leading to reduced mental alertness. 4. Dulling of Emotional Pain: ○ Mechanism: Mu receptors in the limbic system and frontal lobe mediate the dulling of emotional pain. ○ Effect: Opioids can reduce the emotional distress associated with pain, providing a sense of numbness to emotional suffering Opioids: Tolerance & Dependence Key Points: Tolerance Development: 1. Tolerance develops to the following effects: Respiratory depression Analgesia (pain relief) 2. 3. Types 1. 2. 3. Sedation  Euphoria Tolerance does not develop to constipation or pupil constriction. Pupil constriction tolerance is rare. of Tolerance: Intermittent Use: Sporadic use (e.g., drug-free periods between usage). Minimal tolerance development. Regular Weekend Users: Tolerance develops over approximately 1 year of use. Daily Use: Rapid tolerance develops within 8–10 days. As tolerance develops, consumption increases 10-fold. High doses in regular users may be lethal to novices due to tolerance. Opioids: Mechanisms of Tolerance: Key Mechanisms: 1. Pharmacokinetic Tolerance: ○ Enzyme Increase: Cytochrome P450 enzymes (especially CYP3A4, CYP2D6, and CYP2B6) increase in number with repeated opioid use. These enzymes are involved in the metabolism of opioids, leading to faster clearance of the drug from the body, reducing its effects over time. As the enzyme activity increases, a higher dose of opioids is needed to achieve the same effect. 2. Pharmacodynamic Tolerance: ○ Receptor Changes: Opioid Receptors: Mu receptors (primarily responsible for analgesia and euphoria) undergo downregulation (a decrease in receptor number) or desensitization (reduced receptor activity) with prolonged use. Delta and Kappa receptors may also experience similar changes, but the Mu receptors are the most involved in opioid tolerance. Result: Over time, the body requires more of the drug to activate these receptors and produce the same response (e.g., analgesia, euphoria). 3. Cross-Tolerance: ○ Opioids and Alcohol: Tolerance to one opioid (e.g., heroin or morphine) can reduce sensitivity to other opioids and even alcohol, which also acts on the GABAergic system and dopamine pathways. Dependence: This occurs because opioids and alcohol share some common neurotransmitter systems, such as GABA and dopamine, leading to reduced effectiveness of these substances after prolonged exposure to one Characteristics of Withdrawal: ​ ○ Initial Symptoms: Restlessness, agitation, yawning, fever, and chills. Deep sleep followed by cramps, limb twitching, and profuse sweating. ​ ○ Peak Symptoms: Symptoms intensify and reach a peak 36-72 hours after the last use. Cease in 5-10 days. ​ ○ Life-Threatening?: Withdrawal is not typically life-threatening but is very uncomfortable. Physical Tolerance: ○ Rapid Development: Tolerance can develop within 2 weeks of daily use. Craving for the drug starts 4-6 hours after the last dose. Physical symptoms follow, including nausea, muscle pain, and sweating. Other Withdrawal Symptoms: ​ ○ Tearing, runny nose, extreme anxiety, irritability, and spontaneous ejaculation. ​ ○ Mild Psychological Changes: Increased blood pressure and heart rate, which can last for up to 6 months. ○ Physical Effects: Loss of body weight and fluids (due to dehydration). Hallucinations may occur, especially with high fevers during withdrawal. Changes in Withdrawal Severity: ○ Recent Increase in Drug Purity: Withdrawal symptoms are more intense today compared to 30 years ago due to higher drug purity. Psychological Dependence: ​ ○ Harder to Treat: Psychological dependence is often more difficult to treat than physical dependence. ​ ○ Treatment Success: Some success with medications like methadone, LAAM, and buprenorphine to help manage withdrawal and reduce cravings