Pain neurobiology: nociceptors, channels and central sensitization

Nociception starts at channels such as Nav1.7 and TRPV1 and is amplified centrally; central sensitization explains allodynia and secondary hyperalgesia, and its mechanisms, like spinal immune signaling, can differ between sexes.

1. Nav1.7 sets nociceptor excitability. Biallelic loss-of-function SCN9A mutations abolish Nav1.7 current and cause congenital inability to experience pain in otherwise healthy people ¹; gain-of-function variants cause primary erythermalgia, burning red extremities ².
2. Nav1.7 also serves smell. It is required for synaptic signaling from olfactory sensory neurons, so Nav1.7-null patients are anosmic ³.
3. CIPA is a different gene. Congenital insensitivity to pain with anhidrosis results from TRKA (NGF receptor) mutations and adds anhidrosis, unexplained fevers, self-mutilation and intellectual disability; it is autosomal recessive ⁴.
4. TRPV1 explains capsaicin. High-concentration capsaicin activates TRPV1 on cutaneous nociceptors, causing burning, then reduces TRPV1-expressing nerve endings, which re-emerge over months ⁵.
5. Central sensitization is CNS amplification. Woolf defines it operationally as amplified neural signaling within the CNS that elicits pain hypersensitivity: lower thresholds (allodynia), heightened responses (hyperalgesia) and receptive-field expansion (secondary hyperalgesia) ⁶.
6. Spinal immune mechanisms differ by sex. In mice, microglia were required for nerve-injury hypersensitivity in males, whereas females relied on adaptive immune cells, likely T cells; microglia-targeting drugs worked only in males ⁷.

Peripheral sensitization cannot account for dynamic tactile allodynia, temporal summation or secondary hyperalgesia; these point to central mechanisms, including pain that continues after the stimulus ends and spreads beyond the injury ⁶.

• Windup is a progressive rise in dorsal horn output during a train of identical C-fiber stimuli, first described by Mendell and Wall in 1965 ⁶.
• Central sensitization outlasts the conditioning input, persisting tens of minutes after it ends, unlike windup ⁶.
• Ketamine inhibits central temporal summation and secondary mechanical hyperalgesia, supporting an NMDA receptor role ⁶.
• Intradermal capsaicin produces tactile allodynia and secondary hyperalgesia used as a human model of central sensitization ⁶.
• Capsaicin 8% treatment is not repeated more often than every 3 months ⁵.
• Congenital inability to experience pain from SCN9A is autosomal recessive; primary erythermalgia from SCN9A is autosomal dominant ¹².
• Cox's families carried homozygous nonsense SCN9A mutations; mutant channels gave currents no greater than background ¹.
• Sorge and colleagues concluded that male animals cannot serve as proxies for females in pain research ⁷.

• Confusing Nav1.7 loss of function with CIPA; sweating and cognition are normal with Nav1.7 loss ¹⁴.
• Equating windup with central sensitization ⁶.
• Expecting an NMDA antagonist to dampen central sensitization without psychotomimetic effects; trials show little therapeutic index ⁶.
• Assuming a target validated only in male animals will work in women ⁷.