In one breath
The body damps its own pain in two overlapping ways. Descending neuronal systems run from frontal cortex and hypothalamus to the periaqueductal gray, then through the nucleus raphe magnus down the serotonergic raphespinal pathway to the dorsal horn, where enkephalin interneurons block the release of substance P; a second, noradrenergic pathway descends from the locus ceruleus. The opioid system works through µ, δ and κ receptors, on which the endogenous endorphins and the drug morphine act pre- and postsynaptically, all reversed by naloxone. On top of these, gate control lets large tactile afferents presynaptically shut the gate on Aδ and C fibers in the dorsal horn, and stress switches the whole apparatus on.
Builds on: Pain pathways and perception · Synapses and synaptic transmission · Leads to: Specific pain syndromes · Neurotransmitters
Two kinds of endogenous analgesia system are recognized: neuronal, that is descending pain-inhibiting pathways, and opioid.
Descending pain modulating systems
- The story began when stimulation of the ventrolateral periaqueductal gray (PAG) in rats was found to produce profound analgesia.
- Other analgesic sites were found afterwards, chiefly the nucleus raphe magnus and the nucleus paragigantocellularis of the medulla.
- Two descending systems are described:
| System | Transmitter | Origin |
|---|---|---|
| Raphespinal | serotonin | nucleus raphe magnus, driven by PAG |
| Ceruleospinal | norepinephrine | locus ceruleus of dorsolateral pons |
- Worth knowing, though not in your pages: your book credits “Raynold”; the usual spelling of the name is Reynolds (1969).
Descending raphespinal serotonergic pathway
Follow it in four links:
- Frontal cortex and hypothalamus → cells of the periaqueductal region of the midbrain.
- PAG → nucleus raphe magnus and nucleus reticularis magnocellularis in the medulla.
- Raphe nucleus → down the cord in the raphespinal pathway. These fibers are serotonergic and end in laminae I, II and V of the dorsal horn.
- In the cord they end mostly on interneurons, which by a presynaptic mechanism block transmission from the primary afferent to the second-order neuron.
- Those interneurons release enkephalins, and enkephalin holds substance P back inside the presynaptic ending. With no substance P, the pain message never crosses the dorsal horn synapse.
Applied: autoinhibition of pain
This pathway is switched on by pain itself. Ascending pain fibers send branches to the PAG and raphe nucleus, so prolonged pain, which keeps driving the ascending pathways, keeps driving the descending brake as well. That is why long-standing pain gradually loses intensity on its own.
Descending ceruleospinal norepinephrinergic pathway
- Cell bodies in the locus ceruleus of the dorsolateral pons.
- These neurons take no input from the PAG — an independent brake, and a favourite one-line viva question.
- Their fibers descend to the dorsal horn and inhibit transmission of nociceptive impulses from the primary afferents.
- Worth knowing, though not in your pages: this noradrenergic limb is the reason tricyclic antidepressants and drugs such as duloxetine relieve neuropathic pain at doses too low to treat depression.
Draw it: the endogenous neural analgesia system
- Draw a vertical outline of brain and cord, and mark four levels: frontal cortex and hypothalamus, midbrain, medulla, spinal dorsal horn.
- Arrow down from cortex and hypothalamus to the periaqueductal gray in the midbrain.
- From PAG, arrow to the nucleus raphe magnus (and nucleus reticularis magnocellularis) in the medulla.
- From the raphe nucleus, a long raphespinal arrow down to the dorsal horn; label it serotonergic and mark its endings in laminae I, II, V.
- Beside it, a second arrow from the locus ceruleus in the pons to the dorsal horn; label it noradrenergic, and show that no arrow reaches it from the PAG.
- Blow up the dorsal horn synapse: primary afferent ending, second-order neuron, and an interneuron releasing enkephalin onto the afferent ending. Mark the block on substance P release.
- Add an upward arrow of the ascending pain pathway branching into PAG and raphe, labelled autoinhibition.
Endogenous opioid systems
- Morphine acts at the synapses of the nociceptive pathways by binding opiate receptors, and that binding lowers the synaptic excitability of the nociceptive neuron.
- Three major classes of opiate receptor: µ, δ and κ. All three genes belong to the G-protein-coupled receptor family. The µ receptor is where morphine acts as a powerful agonist.
| Site of action | Mechanism |
|---|---|
| Postsynaptic | K⁺ conductance rises in the postsynaptic membrane → inhibition |
| Presynaptic | substance P release blocked at the sensory nerve terminal |
- Opiates therefore inhibit transmission from both Aδ and C fibers.
- Both actions are undone by naloxone, the narcotic antagonist, which occupies the µ receptor.
- Acupuncture and acupressure produce analgesia partly by making the body release its own opioids.
Endorphins
-
The opioid peptides the body makes for itself are called endorphins, meaning endogenous morphine-like substances.
-
The important ones:
- enkephalins — leu-enkephalin and met-enkephalin
- β-endorphin and γ-endorphin
- dynorphin
- α-neoendorphins
-
Their receptors are concentrated in the spinal cord, the PAG of the midbrain and the raphe nucleus of the medulla — exactly the stations of the descending analgesia pathway.
-
Released from different parts of the brain by different stimuli, endorphins give profound analgesia.
Morphine is not an endorphin
Your book’s sentence calls morphine “a potent endogenous analgesic peptide”. Morphine is neither. It is a plant alkaloid from the opium poppy, given from outside, and it is not a peptide. The endorphins are the endogenous peptides. What the sentence means to say is that morphine is a potent analgesic acting at the same receptors.
Applied: addiction and tolerance
The great drawback of opioids is that long use brings addiction and tolerance, and the mechanisms are not settled. Tolerance is thought to follow uncoupling of the opioid receptor from its G proteins. A protein called β-arrestin-2, which phosphorylates the G protein, is held responsible for addiction but not for tolerance.
Gate control theory of pain
- The claim: pain can be modulated peripherally, because the cord can gate the impulses passing through it.
- Collaterals from the large myelinated afferents that carry touch produce presynaptic inhibition of the Aδ and C fibers in the dorsal horn.
- So traffic in the large tactile fibers works as a gate, deciding how much of the pain receptors’ output gets through.
- Acupuncture analgesia works by both mechanisms: the gate, and the release of endorphins.
Applied: acupuncture
The needle goes in at a distant but specific site, not at the painful spot, and the anatomical link between the two is still unknown. Two mechanisms are proposed: endorphin release and the gate control mechanism.
- Worth knowing, though not in your pages: gate control was put forward by Melzack and Wall in 1965, and lamina II, the substantia gelatinosa, is where the gate sits. Rubbing a banged elbow and a TENS machine both work by closing this gate.
Stress-induced analgesia
- Under stress a person’s reaction to pain is suppressed, and the result is analgesia.
- It works by both opioid and non-opioid mechanisms.
- Stress activates the descending analgesia systems.
Don't mix the three brakes
- Descending systems: from the brain down, chemical (5-HT, NE, enkephalin).
- Opioid system: receptors and peptides, acting at those same synapses.
- Gate control: entirely segmental, touch fibers against pain fibers, no brain needed.
Exam-answer skeleton: "Trace the endogenous analgesia pathway with a labelled diagram and add a note on opiate receptors" (long essay)
- Why the body needs it, and the two families: neuronal (descending) and opioid.
- The discovery: PAG stimulation gives profound analgesia; the other analgesic sites, raphe magnus and paragigantocellularis.
- The raphespinal serotonergic pathway traced link by link, with the labelled diagram: cortex and hypothalamus → PAG → raphe magnus → dorsal horn laminae I, II, V.
- The dorsal horn synapse: enkephalin interneurons, presynaptic block of substance P release; autoinhibition of pain in chronic pain.
- The ceruleospinal noradrenergic pathway: locus ceruleus, no PAG input, dorsal horn inhibition.
- Opiate receptors: µ, δ and κ, all G-protein coupled; morphine an agonist at µ; presynaptic and postsynaptic actions; naloxone reverses them.
- Endorphins: the list, and where their receptors are concentrated; acupuncture; addiction and tolerance on long use.
- Gate control theory, and stress-induced analgesia.
Asked in exams
- The body’s own pain control (analgesia system): Jul 2019, 4 marks · Jan/Feb 2022, 4 marks