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Opioid System
Opioid System
Peripheral Innervation
Free nerve ending
- A noxious stimulus triggers an electrical impulse along a free nerve ending.
- We discuss nerve endings in our Sensory System tutorial.
Glutamate & Substance P
- The main excitatory neurotransmitters in pain transmission are glutamate and substance P.
Postsynaptic neuronal dendrite
- These neurotransmitters activate ligand-gated sodium channels along a postsynaptic neuronal dendrite, which propagates the action potential along the postsynaptic neuron.
- The presynaptic neuron produces an excitatory response on the postsynaptic neuron, which itself will excite the thalamus.
Opioid Receptors: Cellular Biology
G-coupled protein receptors
- This pathway is physiologically silenced through endogenous opioid peptides and can be manipulated through pharmacotherapeutics via the opioid system.
- Opioid receptors are G-coupled protein receptors (7-transmembrane helices).
- They have seven membrane-spanning alpha helical segments, attached and separated by loop regions that enter the intracellular and extracellular spaces.
- As such, these opioid receptors have many different downstream effects. There are different subtypes of opioid receptors and pharmacologists are continually trying to exploit the differences in these opioid receptors in order to activate pain ameliorating properties without also triggering untoward side effects, such as respiratory depression and reduction of gastrointestinal peristalsis (which can lead to bowel obstruction); and addictive properties of opioids, such as euphoria and tolerance.
Four Opioid receptors
Mu receptor: endorphins
- The common opioid receptor is the mu receptor. The naturally occurring opioid peptide (endogenous peptide) with the highest affinity for the mu receptor are the endorphins.
- Indeed, the bulk of what is written about opioid receptors and endogenous opioid peptides is about mu receptors and endorphins.
Delta receptor: enkephalins
- Delta receptor: enkephalins have the highest affinity for them.
Kappa receptor: dynorphins
- Kappa receptor: dynorphins have the highest affinity for them.
ORL-1 receptor: N/OFQ
- ORL-1 (orphanin opioid-receptor-like subtype 1) receptors. N/OFQ (nociceptin (aka orphanin FQ)) has the highest affinity them.
Opioid Receptors: Neurophysiology
Directly inhibit the noxious stimulus
- Within the periphery, these receptors produce actions that directly inhibit the noxious stimulus, itself.
Inhibit calcium influx channels
- They can inhibit calcium influx channels, which prevents propagation of the action potential and membrane depolarization.
Promote potassium efflux channels
- They promote potassium efflux channels, which hyperpolarizes the membrane and inhibits membrane depolarization.
Disinhibit descending pain modulatory pathways
- Inhibitory opioid receptors on a spinal interneuron can disinhibit descending pain modulatory pathways.
Additional Actions
- They inhibit cyclic adenosine monophosphate (cAMP); activate phospholipase C; and activate mitogen-activated protein (MAP) kinase.
Implications of numerous opioid actions
- Opioids are not the only means of silencing the pain pathway:
- Calcium and sodium channel blockers; activators of potassium and chloride channels; and stimulation of descending modulatory neurons via psychological or electrical stimulatory mechanisms, amongst many other mechanisms, all have roles in pain suppression.