Glial cell activation in the spinal-trigeminal system in vivo : implications for basic mechanisms of pain transmission

Glial cells directly participate to the genesis and maintenance of chronic pain, both in the central and in the peripheral nervous system, through their functional cross-talk with pain-transducing neurons. Nevertheless, the whole molecular network at the basis of this neuronto- glia communication is still largely unknown, and the purinergic system is likely to play a key role in close conjunction with other paintransducing systems. No data on this issue are currently available in animal models of trigeminal sensitization. Thus, we set up a subchronic inflammatory model in vivo, characterized by inflammatory pain and trigeminal hypersensitivity, by injecting Complete Freund adjuvant (CFA) into the temporomandibular joint (TMJ) of rats. Glial cell activation was evaluated in the trigeminal-spinal system. CFA-injected animals showed ipsilateral mechanical allodynia and TMJ edema. In the trigeminal ganglion, this was paralleled by a strong increase in the number of reactive satellite glial cells encircling neurons and by the activation of resident macrophages. Seventy-two hours after CFA injection, activated microglial cells were observed in the ipsilateral trigeminal subnucleus caudalis and in the cervical dorsal horn, with a significant up-regulation of Iba1 immunoreactivity, with no signs of reactive astrogliosis. As the purinergic system has been implicated in the activation of microglial cells during neuropathic pain, we have also evaluated the expression of the microglial-specific P2Y12 receptor subtype. No upregulation of this receptor was detected following induction of TMJ inflammation, suggesting that any possible role of P2Y12 in this specific model of inflammatory pain does not involve changes in receptor expression (Villa et al., 2010. Mol Pain 6:89). We are now evaluating the proalgogenic or antialgogenic role of specific P2Y-receptor subtypes through their selective inhibition in vivo. Our data suggest that specific glial cell populations may represent innovative targets for controlling pain during trigeminal nerve sensitization, such as during migraine attacks.