Review of a Proposed Mechanism for the Antinociceptive Action of Botulinum Toxin Type A

Botulinum toxin type A (BOTOX®) has been used to treat pathological pain conditions although the mechanism is not entirely understood. Subcutaneous (s.c.) BOTOX® also inhibits inflammatory pain in the rat formalin model, and the present study examined whether this could be due to a direct action on sensory neurons. BOTOX® (3.5-30 U/kg) was injected s.c. into the subplantar surface of the rat hind paw followed 1-5 days later by 50 mL of 5% formalin. Using microdialysis, we found that BOTOX® significantly inhibited formalin-induced glutamate release (peak inhibitions: 35%, 41%, and 45% with 3.5, 7, and 15 U/kg, respectively). BOTOX® also dose dependently reduced the number of formalin-induced Fos-like immunoreactive cells in the dorsal horn of the spinal cord and significantly (15 and 30 U/kg) inhibited the excitation of wide dynamic range neurons of the dorsal horn in Phase II but not Phase I of the formalin response. These results indicate that s.c. BOTOX® inhibits neurotransmitter release from primary sensory neurons in the rat formalin model. Through this mechanism, BOTOX® inhibits peripheral sensitization in these models, which leads to an indirect reduction in central sensitization.