Prolongation of mechanical hyperalgesia by non nociceptive afferent input

Introduction: It is well known that discharges in afferent nociceptive neurons sensitize nociceptive spinal horn neuron cells. The mechanism of central sensitization represents a physiological process which is reversible after the discharges in nociceptive neurons has subsided. However, in chronic pain conditions a dissociation between peripheral nociceptor activity and sensitization of central neurons can be observed. Despite this the knowledge about the mechanisms contributing to the maintance of central sensitization is very limited. In the present study we investigated in an animal model if after initial C-fiber activation, non noxious afferent input could maintain central sensitization after C-fiber activity has subsided.

Methods: Mechanical hyperalgesia was induced by a single intradermal capsaicin injection in the hind paw in 36 rats. The injection was followed by a two weeks period where different non noxious tactile stimuli were applied to the surrounding area (area of secondary hyperalgesia) of the capsaicin injection site. Behavioral testing was carried out until two weeks after termination of the stimulation period. In a second experiment injection of capsaicin, stimulation, and behavioral testing were performed as described above. At day 4 after capsaicin injection, each animal was given intraperitoneal (i.p.) injections of saline (n=6)/ ketamine (n=6) 15 minutes before stimulation.

Results: Input from low threshold mechanoreceptors maintains central sensitization via a non NMDA dependent mechanism. We found that the stimulation of distinct sensory channels showed significant differences in their ability to maintain central sensitization. Activation of FAII receptors (vibration) is the most sufficient stimulus followed by stimulation of FA I receptors (brush) whereas stimulation of SA I receptors (pressure) do not prolong mechanical hyperalgesia.

Conclusion: This study demonstrates that activation of FA II receptors has the capability to maintain central sensitization initiated by a single injection of capsaicin. The maintance of central sensitization is thereby independent from activity in nociceptive C-fibers, and does not critically dependent on NMDA. This mechanism may play a important role in chronic pain conditions in humans.

Unterstützt durch die Deutsche Forschungsgemeinschaft (DFG Ba 1921/1–3), Novartis Foundation (NF-261), BMBF (01EM01–04), die Alexander von Humboldt-Stiftung und Pfizer Deutschland (unrestricted educational grant)