Anesthesia Pharmacology Chapter 13:  Opioid Pharmacology Advanced Topics

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Structure-Activity Relationships

Opioid Receptor Model

"A proposed model of the ternary complex of µ-receptor with a metal ion and morphine viewed from the lipid-exposed (top) and intracellular (bottom) sides.  Morphine and the metal ion (yellow) are space-filled. The residues that are proposed to be most important for the signal transduction via GPCRs are labelled and shown in the stick representation." image reference: Zhorov and Ananthanarayanan, J.Biomol.Struct. Dyn. 15:631-637, 1998.

 

 

Mu-Opioid Receptor 2D6

 

6Opioid Structural Model generated by the Midas Molecular Graphical Program "It displays interaction networks of highly conserved residues: the red residues form a network of hydrogen bonds while the green residues form a network of aromatic-aromatic interactions. The high conservation of each of these residues suggests that they form a structural scaffold for the helical bundle which is common to many GPCRs." (GPCR: G Protein Coupled Receptors); Note the 7 transmembrane components of the model

 

 

Seven  transmembrane components of the mu opioid model6

 

Analgesia Mechanisms

4Opioid Effects at the Dorsal Horn

Substance P

 

 

Substantia Gelatinosa5

1Morphine Antinocicpetive mechanisms in the CNS (Fig. 10-5, ref 1)

 

"The pain pathway and interventions that can modulate activity at each point"

Gottschalk, A and Smith DS, New Concepts in Acute Pain Therapy: Preemptive Analgesia, American Family Physician, May, 2001 http://www.aafp.org/afp/20010515/1979.html

First figure redrawn with permission by Gottschalk and Smith from: Kehlet H, Dahl JB. The value of "multimodal" or "balanced analgesia" in postoperative pain treatment. Anesth Analg 1993;77:1049.

 

  • Tenth Cranial Nerve:  Vagus

    • 7"...vagus nerve consists of five components with distinct functions"

 

 

 

3Preemptive Analgesia

3"Schematic of preemptive analgesia with an emphasis on preventing sensitization of the nervous system throughout the perioperative period. A typical experience without intervention is shown in A, which depicts pain from the initial surgery and the hypersensitivity that subsequently develops. In B, analgesia (A) administered after sensitization may decrease pain somewhat but has little long-term benefit. Analgesia administered before surgery limits the pain from that stimulus and decreases subsequent hypersensitivity, as shown in C. However, the most effective preemptive analgesic regimen is initiated before surgery and continued throughout the postoperative period, as illustrated in D. Although timing of the intervention is important, it must also be capable of preventing sensitization of the nervous system".

Systems Physiology in Nociception and Antinociception

Synaptic Activity of Transmitter/Modulatory Systems in Nociception and Antinociception

Endogenous Opioids

 

10Lateral and Medial Pain Transmission Systems  (illustration by Seward Hung)

10Initial pain signals are transmitted by C-fibers (thin, unmyelinated nerve fibers) that synapse with spinal cord dorsal horn neurons.  From the dorsal horn, pain information travels by way of the spinothalamic tract to the cerebral cortex for subsequent processing.  Afferent signals (to the brain) are transmitted by a lateral system and the medial system.  The lateral system (A in the figure above) appears to provide higher-center information about injury onset, location and intensity.  This system represents a fast pathway providing input to the thalamus and induces a rapid antinociceptive reaction. The medial system (B in the figure above) represents a system that probably conveys information about injury persistence and level of response induced. 

10Sites for Opioid modulation in nociception (illustration by Seward Hung)

  • 10Responses to pain induce activity in antinociceptive pathways.  This activity begins when pain information transmitted by the spinothalamic tract reaches the brainstem and thalamus (A above).  Activation of periaqueductal gray and the nucleus raphe magnus induces endorphin and enkephalin release and binding to "opioid" receptor systems.  Sympathetic and parasympathetic influences within the spinal cord facilitate inactivation of antinociceptive pathways.  Most of the endorphin and enkephalin receptors (70%) are localized presynaptically, substantial pain signal attenuation occurs before information reaches the dorsal horn (B above).  Such information may be further attenuated by enkephalin-induced dynorphin activity at the level the cord (C above).  

    • Dynorphin activates -type opioid receptors localized on inhibitory interneurons, activation of which induces release of the inhibitory neurotransmitter GABA. The mechanism by which -opioid receptor activation limits spinal cord cellular activity may be by means of closure of  N-type Ca2+ channels.  Interaction of GABA with its receptor results in dorsal horn neuronal hyperpolarization thus impeding transmission of the pain information.  Reduction of visceral pain may occur particularly by this approach.

    • Enkephalin binds to -type opioid receptors which appear on nociceptive neurons when they actively transmit pain information.  Furthermore, these receptors are often localized on presynaptic vesicles that contain neurotransmitter and following release receptor protein is incorporated into presynaptic membrane.  Active nociceptors, because of preferential binding, are therefore more sensitive than inactive nociceptive receptors to endogenous opiates.  This idea may be relevant in explaining how opioid analgesics appear to relieve ongoing pain but do not prevent sensing of pain subsequent to new injuries.

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