Activation of glial cells in the cervical spinal cord and in the trigeminal ganglion following induction of inflammatory pain

It is now well known that glial cells in the central and peripheral nervous system do not merely provide nutrients and trophic support to pain-transducing neurons, but rather directly participate to the genesis and maintenance of chronic pain, through their functional cross-talk with neuronal cells. Thus, the overall aim of the present work was to study the contribution of glial cells in the spinal-trigeminal system to the development and maintenance of inflammatory pain, and to verify whether the purinergic system might be a part of the complex and still largely unknown molecular network at the basis of the neuron-to-glia communication. We therefore set up a sub-chronic 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 (i.e., astrocytes and miroglia in the spinal cord and satellite glial cells in the trigeminal ganglion) activation was then evaluated in the spinal-trigeminal system by immunohistochemistry. CFA-injected animals showed ipsilateral mechanical allodynia and TMJ edema. In the ipsilateral trigeminal ganglion, a highly significant increase in the number of reactive satellite glial cells encircling neurons was also observed, paralleled by activation of resident macrophages. Seventy-two hours after CFA injection, activated microglial cells were evident in the ipsilateral trigeminal subnucleus caudalis and in the cervical dorsal horn, with a significant up-regulation of Iba1 immunoreactivity. Conversely, no signs of reactive astrogliosis were detected, indicating no role for spinal astrocytes in pain transmission, at least at these early time points. Since 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 was detected following induction of TMJ inflammation, suggesting that any possible role of P2Y12 receptor in this specific model of inflammatory pain does not involve changes in its expression. We are now evaluating the pro- or anti-algogenic role of other P2Y receptors through their selective inhibition in vivo. Our data suggest that specific glial cell populations might represent innovative targets for controlling pain during trigeminal nerve sensitization, such as during migraine attacks.