In the descending pain modulation system, periaqueductal grey (PAG) neurons activate raphe-spinal serotonergic and locus coeruleus noradrenergic neurons to inhibit dorsal horn nociception. At the spinal cord, the dominant inhibitory mechanism involves:

• A Direct hyperpolarisation of dorsal horn neurons by serotonin acting on 5-HT3 ionotropic receptors
• B Activation of GABA-B receptors on dorsal horn neurons by descending glutamatergic fibres
• C Presynaptic inhibition of primary afferent C-fibres via enkephalin-releasing interneurons acting on mu-opioid receptors ✓
• D Substance P release from dorsal horn neurons that inhibits wide-dynamic-range neurons via NK1 receptors

Explanation

Descending serotonergic and noradrenergic fibres activate enkephalin-releasing interneurons in the dorsal horn. Enkephalins (met- and leu-enkephalin) bind presynaptic mu- and delta-opioid receptors on primary afferent C-fibre terminals, inhibiting voltage-gated Ca²⁺ channels and reducing substance P and glutamate release. Postsynaptic opioid receptors also hyperpolarise dorsal horn neurons. Serotonin has complex effects (inhibitory and excitatory via different receptor subtypes); 5-HT3 is excitatory. Noradrenaline acts via alpha-2 receptors to produce analgesia. Substance P from C-fibres is pro-nociceptive, not inhibitory.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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