Pain Flashcards
Transmission of pain signals
-sodium channels
-peripheral nervous system preferentially express 3 subtypes of voltage-dependent sodium channels:
-> Nav1.7 (TTX sensitive)
-> Nav1.8 (TTX resistant)
-> Nav1.9 (TTX resistant)
Mutations in pain signaling pathways and what it results in
-Gain-of-function mutations in Nav1.7, Nav1.8 and Nav1.9 cause pain
-Loss-of-function mutations in Nav1.7 result in a loss of pain sensation. This is dangerous because pain is a protective mechanism
-potential therapeutic targets for drug discovery
What is the dysfunction of transmission of pain signals most relevant to?
-dysfunction of pain is particularly relevant to the inflammatory pain and neuropathic pain types
-Nerve injury and inflammation may upregulate expression of sodium channels in periphery neurons:
-> inflammatory pain
-> Neuropathic pain
Pulpitis
-Expression of sodium channels contribute to the pathophysiology of tooth pain
-In inflamed condition, myelinated pain fibers express more sodium channels and lose myelinated sheath
Pain Modulation
-Pain is modulated by two primary types of drugs that work at both periphery and central levels: ANALGESICS and ANESTHETICS
-ANALGESICS refer to a drug that relieves pain without the loss of consciousness
-ANESTHESIA refers to a drug causing the loss of all perception of sensory modalities (numbness)
-Local anesthetics block nerve conduction (e.g. lidocaine blocks voltage-gated sodium channels and causes numbness)
Opiate Analgesia
-The most effective clinically used drugs for producing temporary analgesia and relief from pain
-> Morphine
-> Heroin
-Other exogenous opioids:
->Codeine (prodrug of morphine)
-> Methadone
-> Oxycodone
-> Fentanyl
Opioids are currently the only analgesics for treating severe pain
Endogenous Opioid peptides
-There are three major classes of endogenous (come from within the body) opioid peptides:
->endorphins
-> Enkephalins
-> Dynorphins or
neoendorphins
-Found at various sites and in differing quantities throughout the central and peripheral nervous system
Sources of endogenous opioid peptides
-Nerve cells in the brain and spinal cord produce and secrete opioid peptides as neuromodulators
-Released by pituitary and adrenal glands into the circulation
-Immune cells contain opioid peptides that are released within inflamed tissue and act at opioid receptors on peripheral sensory nerve endings
Opioid Receptors
Central or peripheral terminals of nociceptive afferents contain opiate receptors which exogenous and endogenous opioids could act on
Opioid peptides modulate nociceptive input in two ways:
1) Block neurotransmitter release by inhibiting Ca2+ influx
-> The terminal releases less nociceptive substances such as P &. CGRP
2) Open potassium channels, which hyperpolarizes neurons and inhibits pain fibers to conduct pain signal
Modulation of pain signal: Scratching helps relieve pain, why?
-The Gate Control Theory of Pain: asserts that activation of nerves which do not transmit pain signals, called non-nociceptive fibers, can interfere with signals from pain fibers, thereby inhibiting pain
-Scratching activates low threshold, large diameter Ab fibers which counteracts the transmission of pain signals in the spinal cord
-Transcutaneous Electrical Nerve Stimulation (TENS): TENS employs superficial electrodes to activate large (non-pain) axons at the site of the pain or between the pain and the cord. Because the large axons have a lower threshold for this sort of stimulation, they can be selectively activated
How does gate control theory work?
Presynaptic Mechanism:
-Interneuron release endorphins;
-Pain fiber has opioid receptors at terminals;
-Endorphin binds to and activates opioid receptors at nerve terminal of pain fiber;
-G-proteins are mobilized;
-Ca2+ channels are down-regulated
-less glutamate release –> less excitation of projection neuron
Post Synaptic Mechanism:
-Endorphin binds to and activates opioid receptors at nerve terminal of projection neuron;
-G-proteins are mobilized;
-K+ channels are up-regulated;
-Membrane potential of projection neuron becomes more negative;
-projection neuron becomes more difficult to fire AP
Descending Control of Pain
-another way our nervous system controls pain transmission
-the periaqueductal gray (PAG) activates the rostrak ventromedial medulla (RVM)
-this pathway is a critical essential link between the cortex areas of the brain and spinal cord
Pathway of the descending control of pain
-If the PAG neuron gets stimulated, the PAG activates the RVM and locus coeruleus (CL)
-the off-cells in the RVM projects to opiate interneurons (inhibitory neurons) in the dorsal horn.
-LC cells release noradrenaline in the dorsal horn which depresses pain transmission
-pain transmission is reduced
-PAG also projects to the on-cells in RVM
-the on-cells counteract the effects of the off-cells
-The on-cells are tonically active while the off-cells are normally silent
-the balance between the on and off-cell activity controls the ascending pain information
Overall:
-The RVM has opioid receptors
-opiates facilitate the off-cells while inhibit the on-cells
-the combination suppresses pain transmission in the dorsal horn
Descending pain inhibition
-Stimulation produced analgesia (SPA): electrical stimulation initiates descending pain inhibition from the PAG
-Direct microinjection of opioids initiates descending pain inhibition from the PAG
-Opioids and cannabinoids inhibit pain by enhancing the baseline firing rate of off-cells
-At the level of the spinal cord, opioids can inhibit transmitter release from primary afferent terminals as well as activity of pain transmission neurons
