Background: Hyperalgesia that develops following nerve ligation corresponds temporally and in magnitude with the number of thalamic mast cells located contralateral to the ligature. We tested the possibility that mast cells modulate nociception centrally, similar to their role in the periphery. Methods: We examined the central effect of two hyperalgesic compounds that induce mast cell degranulation and of stabilized mast cells using cromolyn. Results: Thermal hyperalgesia (tail flick) induced by nerve growth factor (NGF, a neurotrophic compound) and mechanical hyperalgesia (von Frey) induced by dynorphin A (1-17) (opioid compound) each correlated with the per cent of thalamic mast cells that were degranulated. Degranulation of these mast cells by the central injection of compound 48/80, devoid of neurotrophic or opioid activity, was sufficient to recapitulate thermal hyperalgesia. Stabilization of mast cells by central injections of cromolyn produced no analgesic effect on baseline tail flick or von Frey fibre sensitivity, but inhibited thermal hyperalgesia produced by compound 48/80 and tactile hyperalgesia induced by dynorphin and by Freund's complete adjuvant. Finally, chemical nociception produced by the direct activation of nociceptors by formalin (phase I) was not inhibited by centrally injected cromolyn whereas chemical nociception dependent on central sensitization (formalin-phase II and acetic acid-induced abdominal stretches) was. Conclusions: These convergent lines of evidence suggest that degranulation of centrally located mast cells sensitizes central nociceptive pathways leading to hyperalgesia and tonic chemical sensitivity. Significance: Hyperalgesia induced by spinal nerve ligation corresponds temporally and in magnitude with degranulation of thalamic mast cells. Here, we provide evidence that hyperalgesia induced by NGF, formalin and dynorphin also may depend on mast cell degranulation in the CNS whereas cromolyn, a mast cell stabilizer, blocks these effects in mice.
Bibliographical noteFunding Information:
This work was funded by NIH Grant AR056092 (to A.A.L.) from the National Institutes of Arthritis and Musculoskeletal and Skin Diseases.