Nociception
The sensory process by which the nervous system detects and transmits pain signals from potentially damaging stimuli. Multiple peptide systems modulate nociception, including endogenous opioid peptides. Difelikefalin targets peripheral nociceptive pathways without crossing the blood-brain barrier.
Technical Context
Nociceptive signals begin when nociceptors (free nerve endings expressing transient receptor potential channels — TRPV1, TRPA1 — and voltage-gated sodium channels) detect harmful stimuli. Signals travel via Aδ fibres (fast, sharp pain) and C fibres (slow, burning pain) to the dorsal horn of the spinal cord, where they synapse with second-order neurons. Ascending pathways relay signals to the thalamus and cortex (pain perception) and brainstem (autonomic responses). Descending modulatory pathways from the periaqueductal grey and rostroventromedial medulla can inhibit or facilitate nociception using endogenous opioid peptides, serotonin, and norepinephrine. Difelikefalin acts on peripheral kappa opioid receptors on primary afferent neurons and immune cells in the skin, reducing pruritic and nociceptive signalling at its source.