Peripheral formalin injury induces 2 stages of microglial activation in the spinal cord.

UNLABELLED: The formalin test produces 2 well-known acute phases of nociceptive behavior. Recently, we have shown that this same formalin test produces a third phase of nociceptive behavior consisting of prolonged thermal and mechanical hyperalgesia beginning days after formalin injection and lasting for at least 3 weeks. Here we investigated the activity of 3 MAPKs (p38, ERK and JNK) in the spinal dorsal horn following 5% formalin injection into rat hind paw. The p38 MAPK was rapidly activated in the spinal microglia minutes after injection and the activation persisted for 1 hour. In addition, this same injury induced a secondary increase of phospho-p38 expression in spinal microglia that was maximal 3 to 7 days postinjection. Intrathecal administration of p38 inhibitor SB203580 not only inhibited the early acute spontaneous nociceptive behaviors, but also inhibited the long-term formalin injury-induced mechanical hyperalgesia. Our results suggest that peripheral formalin injection induces 2 stages of microglial activation, and p38 activation in spinal microglia plays key roles in central pain modulation in formalin test respectively for the early acute phases and the late secondary long-term pain state as well. PERSPECTIVE: This article presents unique properties of spinal microglial activation in a pain animal model. This finding could potentially help clinicians to further understand the contributions of spinal microglia to acute and chronic pain state.

Forebrain overexpression of CaMKII abolishes cingulate long term depression and reduces mechanical allodynia and thermal hyperalgesia.

Activity-dependent synaptic plasticity is known to be important in learning and memory, persistent pain and drug addiction. Glutamate NMDA receptor activation stimulates several protein kinases, which then trigger biochemical cascades that lead to modifications in synaptic efficacy. Genetic and pharmacological techniques have been used to show a role for Ca2+/calmodulin-dependent kinase II (CaMKII) in synaptic plasticity and memory formation. However, it is not known if increasing CaMKII activity in forebrain areas affects behavioral responses to tissue injury. Using genetic and pharmacological techniques, we were able to temporally and spatially restrict the over expression of CaMKII in forebrain areas. Here we show that genetic overexpression of CaMKII in the mouse forebrain selectively inhibits tissue injury-induced behavioral sensitization, including allodynia and hyperalgesia, while behavioral responses to acute noxious stimuli remain intact. CaMKII overexpression also inhibited synaptic depression induced by a prolonged repetitive stimulation in the ACC, suggesting an important role for CaMKII in the regulation of cingulate neurons. Our results suggest that neuronal CaMKII activity in the forebrain plays a role in persistent pain.