The effect of connexin 36 deletion on chemotherapy-induced peripheral neuropathy (CIPN).

1 Background: CIPN is a debilitating side effect and dose limiting toxicity of many chemotherapeutic agents. CIPN induces pathological changes in dorsal root ganglia (DRG), leading to increased cross-talk among the glia that surround sensory neurons (Satellite Glial Cells, SGC’s) and between sensory neurons and their adjacent SGCs via gap junctions. Since Connexin 36 (Cx36) is the main neuronal gap junction protein, we investigated CIPN in mice with deletion of Cx36. Methods: To induce CIPN, mice were given two i.p. oxaliplatin (oxa) injections 2 days apart. Controls received saline (sal). We used transgenic mice, which were either heterozygous for Cx36 or complete Cx36 knockouts (Cx36 Het or Cx36 KO), and littermate controls (Cx36 wildtype), 6-14 per group. Tactile sensitivity of the hindpaws was assessed prior to and every week after injections for 4 weeks using von Frey filaments. The number of paw withdrawals to 10 stimulations with each filament and pain thresholds (corresponding to filament that elicits 8/10 responses) were recorded. Results: Oxa-injected wildtype mice had higher response rates to filaments compared to sal-injected controls (p < 0.05), and lower tactile thresholds (at 9 days: sal 6.0±0.0g vs. oxa 1.9±0.5g, p < 0.0001), indicating hypersensitivity. Compared with wildtype, mice lacking Cx36 (Cx36 KO) displayed significantly less tactile hypersensitivity after oxa (tactile threshold at 9 days: WT 1.9±0.5g vs. KO 4.0±0.4g, p < 0.01), whereas oxa induced tactile hypersensitivity occurred in a similar fashion in Cx36 Het mice (tactile threshold at 9 days: WT 1.9±0.5g vs. Het 1.5±0.1g). At 9 days, there were fewer responses to filaments in oxa-injected Cx36 KO mice compared to oxa-injected wildtype mice (p < 0.05), but not in oxa-injected Cx36 Het mice. Conclusions: We found that oxaliplatin induces transient CIPN, represented by tactile hypersensitivity, in wildtype mice. Deletion of the gap junction protein Cx36, as displayed in the Cx36 KO mice, resulted in significantly less CIPN. This is the first report that a neuronal gap junction protein may modulate pain sensitivity, and points to a new molecule (Cx36) as a potential novel target for CIPN therapy.