Differential involvement of reactive oxygen species in a mouse model of capsaicin-induced secondary mechanical hyperalgesia and allodynia

Intradermally injected capsaicin induces secondary mechanical hyperalgesia and allodynia outside the primary (i.e., capsaicin-injected) site. This secondary mechanical hypersensitivity is attributed to central sensitization in which reactive oxygen species (ROS) play a key role. We examined whether ROS would be differentially involved in secondary mechanical hyperalgesia and allodynia using a mouse intraplantar capsaicin injection model. In mice, capsaicin-induced secondary mechanical hyperalgesia outlasted its allodynia counterpart. Unlike the hyperalgesia, the allodynia was temporarily abolished by an anesthetic given at the capsaicin-injected site. The ROS scavenger phenyl-N-tert-butylnitrone slowed the development of both secondary mechanical hyperalgesia and allodynia when administered before intraplantar capsaicin injection, whereas it inhibited only the allodynia when administered after capsaicin had already induced secondary mechanical hyperalgesia and allodynia. Intrathecal injection of the ROS donor KO₂ induced both mechanical hyperalgesia and allodynia with the former outlasting the latter. Metformin, an activator of redox-sensitive adenosine monophosphate-activated protein kinase, selectively inhibited capsaicin-induced secondary mechanical allodynia and intrathecal KO₂-induced mechanical allodynia. These results suggest that ROS is required for rapid activation of central sensitization mechanisms for both secondary mechanical hyperalgesia and allodynia after intraplantar capsaicin injection. Once activated, the mechanism for the hyperalgesia is long-lasting without being critically dependent on ongoing afferent activities arising from the capsaicin-injected site and the continuous presence of ROS. On the contrary, the ongoing afferent activities, ROS presence and adenosine monophosphate-activated protein kinase inhibition are indispensable for the maintenance mechanism for capsaicin-induced secondary mechanical allodynia.