Hierarchical Levels of the Antinociceptive System
The antinociceptive system has a heterogeneous structure and includes three functional levels:
- Brainstem/Spinal (First level). Encompasses structures of the spinal cord, medulla oblongata, and midbrain. It is responsible for the urgent blockade mechanism, interrupting the pain signal immediately upon stimulus application.
- Hypothalamic (Second level). Represented by hypothalamic nuclei. It includes a short-term mechanism that directs descending signals to relay nuclei of the thalamus and spinal cord neurons.
- Cortical (Third level). Localized in the secondary somatosensory cortex. It provides a tonic mechanism that maintains constant background activity of the entire pain control system.
Mechanisms of Descending Inhibition
The basis of the analgesic effect lies in descending inhibition. Signals from higher centers (hypothalamus, cortex) project to brainstem structures, such as the periaqueductal gray matter, raphe nuclei, and locus coeruleus.
From monoaminergic brainstem cells, descending fibers travel down through the dorsolateral funiculus into the spinal cord. In the dorsal horns, these fibers directly or via inhibitory interneurons block the transmission of excitation from primary sensory neurons. Thus, pain impulse conduction is attenuated or completely interrupted at the level of the first synapse ("gate control").
Neurochemistry of Pain Suppression
Pain suppression is implemented through several neurochemical systems:
- Opioid System. Endogenous opioids (endorphins and enkephalins) bind to opioid receptors, decreasing the sensitivity of second-order neurons to pain mediators (glutamate, substance P). Opioid deficiency leads to spontaneous pain, which underlies withdrawal syndrome in substance dependence.
- Serotonergic System. A potent non-opioid mechanism associated with the activity of the nucleus raphe magnus. It exerts a direct descending inhibitory effect on the spinal cord. Unlike opioid analgesia, the effect of serotonin is not blocked by naloxone.
- Non-opioid Peptides. Substances such as neurotensin (whose analgesic activity exceeds that of enkephalins by hundreds of times), oxytocin, and cholecystokinin also participate in antinociception.
- Adrenergic System. Mediated by the hypothalamus and reticular formation. It is responsible for stress-induced analgesia, when strong emotions (fear, anger) block pain sensations.