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Pharmacodynamics

• Mechanism of Action:

  • Analgesia: specific receptor binding -- localization:

    • Spinal cord

    • Brain

• Receptor Types:

  • Mu (μ)

  • Delta (δ)

  • Kappa (κ)

  • General Opioid Receptor Characteristics:

    • G protein coupled receptor family

    • Significant amino acid sequence homology

    • Each-receptor: subtypes

      • μ₁, μ₂

      • δ₁, δ₂

      • κ₁, κ₂

  • Receptor types and physiological effects:

    • Mu (μ) :Analgesia, euphoria, respiratory depression, physiological dependence

    • Most opioid analgesics: act at the μ receptor

    • Delta (δ) and Kappa (k): Spinal analgesia

  • Drugs/endogenous opioids: Receptor- type affinity

    • Morphine -- (μ)

    • Pentazocine -- (κ) some (μ)

    • Endogenous opioid peptides:

      • Leu-enkephalin --(δ)

      • Dynorphin --(κ)

• Cellular Action:

  • Opioids: G protein linked-- affecting

    • Ion channel state

    • Intracellular Ca²⁺ levels

    • Protein phosphorylations states

  • Two well-defined opioid actions:

    1. Reduce neurotransmitter release; by closing a voltage-gated Ca²⁺ channel on presynaptic neuronal terminals Or

    2. Inhibit postsynaptic neurons (hyperpolarization) by increasing and K⁺ channel conductance

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    Spinal Cord Sites of Opioid Action

     

     

• Spinal cord presynaptic sites:

  • Reduced transmitter released affecting acetylcholine, norepinephrine, glutamate, serotonin, substance P systems.

    • Serotonin, bradykinin, histamine, prostaglandins, substance P (sP) , and various ions (ie, H+ or K+), the biochemical mediators released as a result of tissue injury, have been implicated in nociceptive activation and sensitization (hyperalgesia). Hyperalgesia results in enhancement of spontaneous pain via a reduction in pain threshold and a lengthening in duration of nociceptor response to stimuli. PGE1, PGE2, and PGF2a, are the most potent prostaglandins to produce these sensitization effects. Substance P, synthesized by cells of the spinal ganglia, has been identified at the peripheral terminal of unmyelinated primary afferent fibers. This putative neurotransmitter may play a role in the propagation of visceral nociceptive pain from the gastrointestinal (GI) tract, ureters, and urinary bladder.  In addition, to sP, other potential nociceptive transmitters include glutamate, aspartate, somatostatin, cholecystokinin, and vasoactive intestinal polypeptide. courtesy of Roxane Pain Institute used with permission

• Opioid Receptor Distribution

  • Spinal cord: dorsal horn

  • Primary afferents to pain transmission neurons

    • Opioid agonists:

      • Inhibit excitatory transmitters release from these primary afferents

      • Inhibit dorsal horn pain transmission neurons

      • Clinical application: directed administration of opioid agonists allow regional analgesia which minimizes CNS side effects

  • "C Fibers are small, unmyelinated nerves with slow conduction velocities that carry dull, aching burning pain impulses. Thinly myelinated A afferent fibers carry fast, sharp, shooting pain sensations and are most integral to the propagation of mechanical pressure stimuli from muscles, joints, and bone. Compared with these fibers, C afferent fibers have a higher threshold for mechanical stimuli and a smaller field of reception. Both these classes of nociceptive fibers ultimately synapse with neurons in the dorsal horn of the spinal cord." courtesy of Roxane Pain Institute used with permission

• Systemic Opioid Administration:

  • Action in both supraspinal and spinal sites

    • "Transmission of impulses, which as they reach consciousness will be interpreted as pain, begins with the activation of specific peripheral receptors called nociceptors by disease- or surgery-induced tissue injury. Nociceptors usually respond to high intensity, potentially damaging stimuli. Inflammatory processes often associated with disease or tissue trauma play a role in the initiation of nociception, mostly by sensitizing the nociceptors: which causes lowering of their activation threshold. Both A- and C-class nociceptors and their corresponding afferent fibers are the most important carriers of nociceptive stimuli from the skin, deep somatic structures, such as muscle and bone, and viscera. On going nociceptor-evoked discharges carried by these afferent fibers enter the spinal cord via the dorsal roots, extending into several ascending nociceptive pathways. The dorsal horn is not only a relay station for these signals, but also an area in which complex data integration of excitatory or inhibitory modulation occurs." courtesy of Roxane Pain Institute used with permission

  • Important opioid binding sites in descending pathways

    • Rostral ventral medulla

    • Locus ceruleus (see below)

    • Midbrain periaqueductal gray

  • Administration of exogenous opioids promotes release of endogenous opioids

  • Sagittal Brain View:  Anatomy Reference

    Reticular formation (RF), vestibular nuclei (V), cerebellar roof nuclei (R), periaquiductal gray (PG).  Posterior hypothalamic nuclei (P), paraventricular hypothalamic nucleus (PV), substantia nigra (SN),  Thalamic nuclei (T), preoptic hypothalamic nuclei (PO), locus ceruleus (LC), median raphe nuclei (MR) .

• Tolerance/Physical Dependence

  • Repeated opioid administration results in a gradual loss of effect, e.g. tolerance

  • Physical Dependence = physiological withdrawal symptoms (abstinence syndrome) if an antagonist is administered or the agonist is stopped.

  • Tolerance is not developed equally to all opioid effects.