Which receptor underlies chronic pain

Pain, especially of the chronic variety, is not well controlled by current drugs, and recent clinical trials have been unsuccessful. By seeking genes with expression levels that correlate with a chronic pain–like test in mice, Wieskopf et al . show that we may have set our sights on the wrong target. Transcripts encoding the α6 subunit of the nicotinic acetylcholine receptor were highly expressed when chronic pain was low, and genetic experiments confirmed that this subunit limited pain. The α6 subunit was required for analgesia, whereas the α4 subunit—the target of recent drug development efforts—was not. A human genetic study showing that people with a certain allele in the gene encoding the α6 subunit are at increased risk of chronic pain lends confidence in the clinical relevance of these results. Mechanistically, FRET (fluorescence resonance energy transfer) detected an interaction between nicotinic receptors with the α6 subunit and the purinergic receptors P2X3 in cultured cortical mouse neurons. Coexpression of various combinations of α6-containing nicotinic receptors with P2X2 and P2X3 in Xenopus oocytes suggested that, when ligands for both types of channels were added, the channels inhibited each other. Injection of an P2X3 agonist into mouse hind paws produced behaviors associated with pain that were ameliorated by nicotine, but this nicotine-mediated reduction in pain was absent in the α6-knockout mice. Thus, enhancing activity of the α6-containing nicotinic acetylcholine receptors may be helpful in treating chronic pain. J. S. Wieskopf, J. Mathur, W. Limapichat, M. R. Post, M. Al-Qazzaz, R. E. Sorge, L. J. Martin, D. V. Zaykin, S. B. Smith, K. Freitas, J.-S. Austin, F. Dai, J. Zhang, J. Marcovitz, A. H. Tuttle, P. M. Slepian, S. Clarke, R. M. Drenan, J. Janes, S. Al Sharari, S. K. Segall, E. K. Aasvang, W. Lai, R. Bittner, C. I. Richards, G. D. Slade, H. Kehlet, J. Walker, U. Maskos, J.-P. Changeux, M. Devor, W. Maixner, L. Diatchenko, I. Belfer, D. A. Dougherty, A. I. Su, S. C. R. Lummis, M. I. Damaj, H. A. Lester, A. Patapoutian, J. S. Mogil, The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors. Sci. Transl. Med. 7 , 287ra72 (2015). [Abstract]