This suggests that the ability of nalbuphine to reduce morphine-induced itch is largely due to its KOR agonist activity. Consistent with this, KOR agonists have been shown to

reduce morphine-induced itch in monkey (Ko et al., 2003). These findings raise the possibility that coadministration of mu and kappa opioids (or the use of agonists with affinities for both receptors) may offer pain relief without causing itch. STAT inhibitor An important question raised by our study is the identity of the dorsal horn neurons that respond to kappa opioids. KORs have been detected on some neurons in laminae I-II (Arvidsson et al., 1995), and approximately 15% of lamina II neurons are hyperpolarized by kappa opioids (Eckert and Light, 2002 and Peckys and Landwehrmeyer, 1999). While we do not yet know the identity of these cells, our finding that GRP-evoked itch is attenuated by nalfurafine is consistent with the idea that kappa opioids directly inhibit GRPR-expressing spinal interneurons.

Compound C concentration Alternatively, kappa opioids may act downstream, targeting as-yet-unidentified interneurons or projection neurons that mediate itch. Identifying the dorsal horn neuronal subtype(s) that express the KOR will be of great interest, as these cells may represent a point of convergence between neural circuits mediating itch and those responsible for inhibition of itch by counterstimuli. Several clinical trials have shown that nalfurafine is effective in reducing itch in patients with chronic renal failure (Kumagai et al., 2012 and Wikström et al., 2005). Furthermore, nalfurafine is well tolerated, and dysphoria is not reported even after 1 year of treatment. Our study provides insight into the mechanism through which kappa agonists inhibit itch, raising the possibility until that this class of drugs may be broadly applicable as antipruritics. Thus, kappa agonists may have therapeutic potential for the treatment of pruritus resulting from a wide range of dermatological and systemic diseases. Most behavioral tests were carried out on 6- to 8-week-old male C57bl/6 mice. Experiments that involved Bhlhb5−/− mice ( Ross

et al., 2010) were performed on 4- to 5-week-old mice that did not have skin lesions, unless otherwise stated. To generate age-matched wild-type and Bhlhb5−/− mice, we harem mated Bhlhb5−/+ mice and wild-type and Bhlhb5−/− offspring from the resulting litters were used. In all experiments, the observer was blind to genotype and/or treatment. The use of animals was approved by the Institutional Animal Care and Use Committee of the University of Pittsburgh and/or the Ethical Review Process Applications Panel of the University of Glasgow. Experiments performed in A.J.T.’s lab were in accordance with the UK Animals (Scientific Procedures) Act 1986. Further details are provided in the Supplemental Experimental Procedures. Immunocytochemistry was performed using standard protocols.