Vertical organization of the system
The anti-pain (antinociceptive) and nociceptive (pain) systems have a clear vertical hierarchy consisting of five main anatomical levels. Each of these levels performs a specific task in the perception or suppression of pain:
- Cerebral cortex. Serves as the highest center. This is where pain is ultimately perceived and its emotional evaluation is formed.
- Thalamus. Acts as a sensory relay station. It collects all incoming information and relays pain impulses directly to the cortex.
- Midbrain. Contains the key structure for endogenous analgesia — periaqueductal gray (also known as the central gray matter).
- Medulla oblongata. This level houses critical nuclei of the reticular formation. These include the locus coeruleus, which is the source of descending noradrenergic pathways, and the nucleus raphe magnus, the source of serotonergic pathways.
- Spinal cord. The dorsal horn level is the site of primary switching for pain impulses arriving from the periphery.
Ascending pain pathway
To understand how pain relief works, it is necessary to examine the mechanism of afferentation — the transmission of pain signals.
A pain impulse originates in the periphery and enters the dorsal horns of the spinal cord. Here, primary switching to ascending neural pathways takes place. Along these pathways, the signal ascends to the thalamus and is projected from there to the cerebral cortex.
The main function of this ascending pathway is the formation of the pain sensation itself (perception) and imparting a specific emotional coloring to it. Under normal conditions, signal transmission proceeds unhindered; however, when analgesics are administered (e.g., during morphine blockade), this pathway is interrupted.
Descending inhibition mechanism
The antinociceptive system operates strictly top-down. It is activated to block the entry of new pain impulses at the spinal cord level.
The process of descending endogenous analgesia occurs in several stages:
- Activation. Neural impulses from the periaqueductal gray in the midbrain are directed downward to structures of the medulla oblongata.
- Modulation. In the medulla oblongata, these impulses activate neurons of the locus coeruleus and the nucleus raphe magnus.
- Effector phase. Activated descending fibers reach the dorsal horns of the spinal cord, where they release inhibitory neurotransmitters — norepinephrine (NE) and serotonin (5-HT).
- Pain blockade. The released neurotransmitters act on specialized interneurons. These interneurons, in turn, release enkephalins (ENK) — endogenous opioid peptides. Enkephalins bind to opioid receptors and reliably inhibit the further conduction of the pain signal.
Neurochemical organization
A specific set of neurotransmitters and receptors is involved in the transmission and modulation of pain signals.
To suppress pain, the body uses norepinephrine and serotonin, which provide descending inhibition. Enkephalins effect direct blockade. Opioid receptors, which enkephalins (and exogenous opiates) interact with, are localized not only in the spinal cord but also at other levels of the pain system, including the thalamus and midbrain.
Briefly: answers to topical questions
What exogenous pharmacological agents, other than morphine, interact with the antinociceptive system?
In addition to morphine, other opioid and non-opioid drugs interact with the antinociceptive system.
- Buprenorphine — a partial μ-opioid receptor agonist.
- Pentazocine — an opioid receptor agonist-antagonist.
- Fentanyl and omnopon — opioid analgesics; omnopon is a full agonist.
- Nalbuphine — an agonist-antagonist.
- Naloxone and naltrexone — opioid receptor antagonists.
- Clonidine — a drug whose effects are mediated by stimulation of α₂-receptors in the CNS.
- Carbamazepine and gabapentin — antiepileptic drugs (anticonvulsants).
- Amitriptyline — a tricyclic antidepressant.
To remember the descending pathway: "PAG (Midbrain) commands the Colored nuclei (Locus coeruleus and Nucleus raphe magnus) to douse the fire of pain in the Dorsal horns of the spinal cord with norepinephrine and serotonin."
Class and exam questions
Where does primary switching of the pain impulse occur?
Primary switching of the pain signal coming from the periphery occurs in the dorsal horns of the spinal cord.
Which neurotransmitters are involved in descending pain inhibition?
Descending inhibition involves norepinephrine (from the locus coeruleus), serotonin (from the nucleus raphe magnus), and enkephalins (released by spinal interneurons).
Where are opioid receptors localized?
Opioid receptors are located at various levels of the system: in the spinal cord, midbrain, and thalamus.
What else to study on this topic
- The role of the periaqueductal gray
- Functions of the locus coeruleus and nucleus raphe magnus
- Interaction of enkephalins with opioid receptors
- Effect of morphine on ascending pain pathways
- The role of the thalamus as a sensory relay station
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