: drugs that cause analgesia without loss of consciousness (morphine – like actions). 3 distinct families of naturally occurring opioid peptides: endorphins, enkephalins, and dynorphins. These peptides are derived from different genes and have different localizations in the CNS.
Naturally occurring opioid peptides
(1) Pro-opiomelanocortin (POMC)
Localization
– primarily in the corticotrophs of the anterior pituitary, melanotrophs of the intermediate pituitary, and neurons of the arcuate nucleus and dorsal medial nucleus of the hypothalamus.
Synthesis
– POMC is a larger precursor peptide which undergoes tissue-specific post-translational processing into:
melanocyte stimulating hormone (MSH) and ß-endorphin
(Pituitary – Intermediate lobe)
MSH
(arcuate and dorsal medial nuclei of the hypothalamus)
Role in pain perception
– anatomy of hypothalamic neurons expressing opiates suggests the presence of a hypothalamic feedback circuit involved in higher order perception and modulation of sensory information as well as producing either appropriate or maladaptive levels of arousal based on the perceptions of sensory stimulation.
(2) Proenkepalin
Localization
– more widely distributed than POMC. Found in areas presumably related to the perception of pain.
Processing
– leucine and methionine enkephalin. These pentapeptide sequences are found within the sequences of both POMC and dynorphin but the enkephalins are not products of these precursors.
Role in pain perception
– local modulation of sensory and visceroceptive information.
(3) Prodynorphin
Localization
– Restricted. Found primarily in the mossy fibers arising from granule cells of the dentate gyrus in the hippocampus, deep layers of the cerebral cortex and caudate-putamen-globus pallidus.
Processing:
into dynorphin A and B and a – and ß-neoendorphin.
Role in pain perception:
modulate perception, affect and arousal, and mediate sedation seen following opiate administration.
Mechanisms of Opioid Action
Opioid receptors
Several classes: m, k, and d. (each class has multiple members)
High affinity between:
(1) endorphins – m receptors
(2) enkephalins – d receptors
(3) Dynorphins – k and m receptors.
Opioid has highest affinity for m receptors.
Naloxone (an opiate antagonist)
binds to the m , k , and d receptors
Receptor mechanisms
:
All exert inhibitory modulation of synaptic transmission (i.e. reduces transmitter release)
All appear to be coupled to guanine nucleotide binding regulatory proteins (G proteins).
Pharmacological Properties
CNS effects – analgesia, drowsiness, anxiety reduction, euphoria, mental clouding, and respiratory depression. Nausea, emesis, and orthostatic hypotension occurs in some cases. Profound effects on several endocrine systems
Peripheral effects
– miosis, inhibition of smooth muscle contraction and increase in smooth muscle tone in G.I. tract, urinary tract, and uterus. ß secretion of HCL, ß gastric motility
Pharmacokinetics
Rapid absorption: GI (but because of first-pass metabolism in the liver oral absoprtion not as effective as IM or subcu). Readily absorbed from Subcutaneous or Intramuscular injection. Does not persist in tissues. ½ life – 2 hours.
Metabolism
– Liver breakdown by conjugation with glucuronic acid. Active and inactive products formed
Þ morphine-6-glucuronide (more potent than morphine)
Tolerance and physiological dependence
Characteristic feature of the opioids: development of tolerance and physical dependence
Development of tolerance: Interactions between opioid and other neurotransmitter pathways.
Opiate poisoning
: triad of coma, pinpoint pupils and depressed respiration
Treatment:
naloxone, an opioid antagonist. Warning: avoid mixed agonist-antagonist (nalorphine, levallorphan) since they can further compromise respiration that has been depressed in mixed poisonings (opiate plus alcohol, barbiturate or benzodiazepine intoxication).
: effective analgesic, well absorbed, 1/2 life – 15-40hrs (used for withdrawl pain from opioids)
The future of pain analgesia:
ABT – 594 – non-opioid analgesic, blocks acute and chronic pain, acts at nicotinic acetycholine receptors, not addictive or toxic
Acute opioid toxicity
: coma, pinpoint pupils, depressed respiration (lethal dosage does not have a tolerance factor)
Other Drugs
Meperidin (Demerol) –
strong opioid receptor agonist, analgesic effect, Ý addiction abuse, accumulation of normeperidine( break down compound) can cause seizures in patients receiving Ý doses