Medical Pharmacology: Opioids

Medical Pharmacology Chapter 13: Pain Management: Opioids

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 (κ): Spinal analgesia
- Drugs/endogenous opioids: Receptor- type affinity
  - Morphine -- (μ)
  - Pentazocine -- (κ) some (μ)
  - Endogenous opioid peptides:
    - Leu-enkephalin --(δ)
    - Dynorphin --(κ)

**Opioid Receptor Subtype**
Drug	Mu (μ)	Delta (δ)	Kappa (κ)
Opioid Peptides
Enkephalins	Antagonist	Agonist
beta-endorphin	Agonist	Agonist
Dynorphin	Weak Agonist		Agonist
Agonists
Codeine	Weak Agonist	Weak Agonist
Etorphine	Agonist	Agonist	Agonist
Fentanyl (Sublimaze)	Agonist
Meperidine (Demerol)	Agonist
Methadone (Dolophine)	Agonist
Morphine	Agonist	Weak Agonist
Agonist-antagonists
Buprenorphine	Partial Agonist
Dezocine (Dalgan)	Partial Agonist	Agonist
Nalbuphine (Nubain)	Antagonist		Agonist
Pentazocine (Talwain)	Antagonist or Partial Agonist		Agonist
Antagonist: naloxone (Narcan)	Antagonist	Antagonist	Antagonist

Cellular Action:
- Opioids: G protein linked, affecting:
  - Ion channel state
  - Intracellular Ca²⁺ levels
  - Protein phosphorylations states
- Two well-defined opioid actions:
  1. Reduction in neurotransmitter release by closing a voltage-gated Ca²⁺ channel on presynaptic neuronal terminals Or
  2. Inhibition of postsynaptic neurons (hyperpolarization) by increasing and K⁺ channel conductance

**Spinal Cord Sites of Opioid Action**

Spinal cord presynaptic sites:
- Reduced transmitter released affects acetylcholine, norepinephrine, glutamate, serotonin, substance P transmitters.

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 PGF_2a, 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

Way, W.L., Fields, H.L. and Way, E. L. Opioid Analgesics and Antagonists, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 496-515.

Schuckit, M.A. and Segal D.S., Opioid Drug Abuse and Dependence, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2508-2512.

Coda, B.A. Opioids, In Clinical Anesthesia, 3rd Edition (Barash, P.G., Cullen, B.F. and Stoelting, R.K.,eds) Lippincott-Ravin Publishers, Philadelphia, New York, 1997, pp 329-358.

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