2060 Chapter 11B

Page 1: Introduction to Opioid Receptors

  • Discovery of Opioid Receptors

    • Identified using radioligand binding methods.

    • Binding of radioactive opioid (e.g., naloxone) increases, reaches a plateau when all receptors are occupied.

    • Binding is reversible, confirming specificity to opioid receptors.

Page 2: Relative Potency of Opioids

  • Competition Experiments

    • Relative potency of various opioids correlates with their effects on intestinal function.

    • Indicates that potency in receptor binding influences physiological outcomes.

Page 3: Opioid Receptor Distribution in the Brain

  • Autoradiography Technique

    • Utilized to visualize opioid receptor distribution in the rat brain.

  • Key Areas of Receptor Distribution

    • Hippocampal Dentate, CA1 gyrus, Cerebral Cortex, Striatum, Olfactory bulb, Midbrain, Thalamus.

Page 4: Opioid Receptor Subtypes

  • Identifying Receptor Subtypes

    • Selective radioligands identify different receptor subtypes: μ, δ, κ, and nociceptin/orphanin FQ receptor (NOP-R).

    • All linked to G proteins, suspected to be metabotropic.

    • Distinct distributions suggest varied physiological effects in brain and spinal cord.

Page 5: Autoradiograms of Opioid Receptor Binding

  • Binding Visualization

    • Figure illustrates binding patterns of opioid receptor subtypes in different brain areas.

    • Distinction between mu (μ), delta (δ), and kappa (κ) receptors clarified.

    • Key areas include Olfactory regions, Striatum, Cortex, Thalamus, Raphe nuclei, and Locus coeruleus.

Page 6: μ-Receptor Characterization

  • Morphine Affinity

    • μ-receptor has high affinity for morphine.

  • Functional Correlates

    • Locations linked to analgesia: medial thalamus, periaqueductal gray, median raphe, spinal cord.

    • Other functions: feeding, positive reinforcement (nucleus accumbens), respiratory depression (brainstem), sensorimotor integration (thalamus, striatum).

Page 7: δ-Receptor Distribution

  • Location Analysis

    • Predominantly in forebrain structures.

  • Functional Roles

    • Modulates olfaction, motor integration, reinforcement, cognitive function.

    • Overlaps with μ-receptors may indicate a role in both spinal and supraspinal analgesia.

Page 8: κ-Receptor Overview

  • Distinct Distribution

    • Initially identified with ketocyclazocine, an opioid analog linked to hallucinations and dysphoria.

  • Regulatory Functions

    • Present in striatum, amygdala, hypothalamus, and pituitary; involved in pain perception, gut motility, dysphoria regulation.

Page 9: NOP-R Characteristics

  • Location and Function

    • Found throughout CNS and PNS, notably in cerebral cortex, limbic areas, thalamus, raphe nuclei, spinal cord.

    • Functions suggested to include analgesia, feeding, learning, motor function, neuroendocrine regulation.

Page 10: Heteromeric Complexes of Receptors

  • Inter-Receptor Interaction

    • Receptor subtypes form heteromeric complexes.

    • Interactions can enhance or diminish the effects of opioid drugs.

    • Targeting μ–δ heteromers can prevent the development of tolerance to chronic morphine.

Page 11: Endogenous Opioid Neuropeptides

  • Discovery and Types

    • Presence of opioid receptors implied existence of endogenous opioid neurotransmitters.

    • 1970s: Identification of endorphins, peptides binding to opioid receptors.

    • Four major propeptides processed into smaller active opioids:

      • Prodynorphin

      • Pro-opiomelanocortin (POMC)

      • Proenkephalin

      • Pronociceptin/orphanin FQ.

Page 12: Propeptides and Their Products

  • Overview of Propeptides

    • Diagrams of the four propeptides and their derivatives, including:

      • Pro-opiomelanocorting (POMC) products: ACTH, β-END, α-MSH.

      • Proenkephalin derivatives: met-ENK and leu-ENK.

      • Prodynorphin splits into dynorphins (DYN-A, DYN-B) and neoendorphins.

Page 13: Propeptides in Pain and Mood Regulation

  • Distribution and Function

    • Concentrated in brain, spinal cord, autonomic nervous system areas that modulate pain and mood.

    • Example: High POMC in pituitary gland releases corticotropin-releasing factor (CRF) during stress.

    • Suggests interplay between pain signaling and stress response.

Page 14: Opioid Receptor Characteristics

  • Table Overview

    • Highlights relative preferences of peptides for receptor subtypes and their functions.

    • Key experiences include analgesia, reinforcement, motor functions linked to specific receptors and endogenous ligands.

Page 15: G Protein Coupling in Opioid Receptors

  • Inhibitory Mechanisms

    • All opioid receptor types coupled to inhibitory G proteins (Gi).

    • G proteins inhibit adenylyl cyclase, decreasing cAMP synthesis.

    • This is associated with changes in ion channel function, playing a role in opioid signaling effects.

Page 16: Mechanisms of Opioid Inhibition

  • Three Modes of Inhibition

    • Postsynaptic Inhibition:

      • G proteins activate to open K+ channels, leading to hyperpolarization.

    • Axoaxonic Inhibition:

      • Closing Ca2+ channels reduces neurotransmitter release.

    • Presynaptic Autoreceptors:

      • Activation leads to reduced release of co-localized neurotransmitters.

Page 17: Diagram of Opioid Actions

  • Visual Representation

    • Illustrates inhibitory effects of endogenous opioids with details on mechanisms for postsynaptic, axoaxonic, and presynaptic inhibition.