Close encounters of the third kind: evidence for contact with TNF-alpha.

If you have not heard that glial cells are involved in pain processing then you have missed some significant advances in our understanding of the generation and maintenance of pain [3]. It is well established that spinal astrocytes and microglial cells become activated after peripheral nerve injury. The stream of incoming primary afferent activity that accompanies such injury bombards the spinal cord with a variety of neurotransmitters, including substance P (Sub-P) (Fig. 1). Microglial cells exposed to Sub-P increase their expression of OX-42 as well as their expression of inflammatory mediators, such as tumor necrosis factor alpha (TNFalpha) and chemokine ligand 2 (CCL2) [1,4]. That this process is involved in the generation of pain is borne out by the finding that preventing or reversing the activation of microglial cells with minocycline reduces nerve injury-associated pain behavior [5]. Consistent with these observations, intrathecal administration of the TNF-alpha inhibitor, etanercept, is antinociceptive.