Nonneuronal central mechanisms of pain: glia and immune response.

The role of central glial cells in the mechanisms underlying pain has been intensively studied in the last two decades. Most studies on glia and pain focused on the potential detrimental role of glial cells following noxious stimulus/insults manifested as an "activation" or a "reactive" state (increase in glial marker expression and production of proinflammatory/nociceptive molecules). Therefore, "activated" or "reactive" glial cells became a target for the future generation of drugs to treat chronic pain. Several glial modulators that reduce the activation of glial cells have shown great efficacy in multiple animal (rodents mostly) models of pain (acute, subacute, chronic, inflammatory, neuropathic, surgical, etc.). These encouraging findings inspired clinical trials that have been completed in the last 5 years. Unfortunately, all clinical trials with these glial modulators have failed to demonstrate efficacy for the treatment of pain. New lines of investigation and elegant experimental designs are shedding light on alternative glial functions, which demonstrate that "glial reactivity" is not necessarily deleterious in some pathological conditions. New strategies to validate findings through our current animal models are necessary to enhance the translational value of our preclinical studies. Also, more studies using human subjects would enhance our understanding of glial cells in the context of pain. This chapter explores the available literature to objectively ponder the potential role of glial cells in human pain conditions.