Glial coupling in systemic insults : possible contribution to chronic pain

Chronic pain is a major clinical problem, but the mechanisms underlying it are still rather obscure, and therapies, which are targeted to neurons, are largely ineffective. There is evidence that central glial cells are altered in pain models, and that these cells can be an effective therapeutic target. We have shown that gap junction (GJ)- mediated coupling among satellite glial cells (SGCs) in sensory ganglia, increased 5-7 fold in mouse pain models, and that blocking GJs reduces pain behavior. Previous work has focused on local injuries such as axotomy, and here we asked whether similar mechanisms operate in systemic insults that cause pain. Using mice, we induced systemic inflammation with lipopolysaccharide (LPS, 2.5 mg/kg), and also produced neuropathy using the cancer drug oxaliplatin (2x4 mg/kg, 3 days apart). Intracellular injections of Lucifer yellow showed that both LPS and oxaliplatin induced a large increase in SGC coupling in dorsal root ganglia. Electron microscopy revealed that LPS induced the formation of bridges between SGCs, where these cells were connected by newly-formed GJs. The expression of the glial marker glial fibrillary acidic protein (GFAP) was enhanced (the number of neurons surrounded by GFAP-positive cells increased 3-fold), consistent with glial activation. Both treatments also caused augmented tactile sensitivity, as tested with von Frey filaments. These changes persisted for about two weeks. Systemic (IP) injection of the GJ blocker carbenoxolone (50 mg/kg), was so far done only after oxaliplatin, and clearly reduced the behavioral pain responses. Following LPS injection, there was a large increase in the sensitivity of SGCs to ATP, acting on P2 receptors. As both GJ and P2 receptors participate in the propagation of calcium waves, the enhanced GJ communication and P2 upregulation may underlie augmented spread of signals within the ganglion. We conclude that local and systemic insults share fundamental similarities in that both induce SGC activation. Furthermore, activation is associated with a large increase in SGC coupling. We propose that glial coupling contributes to chronic pain, and that a potential therapy for pain is the selective blockade of GJ.