• Daniel Ursu, Philip Ebert, Emily Langron, Cara Ruble, Leanne Munsie, Wei Zou, Bonnie Fijal, Yue-Wei Qian, Terry A McNearney, Adrian Mogg, Olivera Grubisha, Kalpana Merchant, and Emanuele Sher.
• Lilly Research Centre, Eli Lilly & Co, Ltd,, Sunninghill Road, GU20 6PH Windlesham, Surrey, UK. sher_emanuele@lilly.com.
• Mol Pain. 2014 Jan 1;10:37.

BackgroundGenetic causes of exaggerated or reduced pain sensitivity in humans are well known. Recently, single nucleotide polymorphisms (SNPs) in the gene P2RX7, coding for the ATP-gated ion channel P2X7, have been described that cause gain-of-function (GOF) and loss-of-function (LOF), respectively of this channel. Importantly, P2RX7 SNPs have been associated with more or less severe pain scores in patient suffering of post-mastectomy pain and osteoarthritis.ResultsThe functional consequences of some P2RX7 SNPs (rs208294 (His155Tyr), rs1718119 (Ala348Thr) and rs3751143 (Glu496Ala)) were studied in recombinant cells in vitro. Our findings suggest a correlation between GOF and LOF of P2X7 and actual channel protein expression. Both channel and pore function for these mutant P2X7 receptors changed in parallel to protein levels. On the other hand, the mutant receptors did not differ in their sensitivity to known P2X7 agonists and antagonists. We further demonstrated that in patients with diabetic peripheral neuropathic pain (DPNP), the presence of the GOF SNPs rs208294 (His155Tyr) and rs1718119 (Ala348Thr) is associated, in females, with higher pain intensity scores.ConclusionsOur present results confirm the physiological relevance of some of the SNPs in the P2RX7 gene and show that the presence of these genetic variants correlates with pain sensitivity also in a diabetic neuropathic pain patient population.

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