Dr. Sam Enna
The Journal of Pharmacology and Experimental Therapeutics
Dear Dr. Enna,
While reviewing the manuscript entitled “Molecular mechanisms of agonist-induced desensitization of the cloned mouse kappaopioid receptor” by K. Raynor, H. Kong, J. Hines, G. Kong, J. Benovic, K. Yasuda, G. I. Bell and T. Reisine published in The Journal of Pharmacology and Experimental Therapeutics (JPET270:1381–1386, 1994), several errors in the figure legends have been identified. The figure 3 legend indicates that the results shown in the figure are from three experiments, whereas the figure only shows the results of one of the multiple experiments performed. The figure 4 legend indicates that the results are from four experiments, whereas the figure shows the average results of three of those experiments. The magnitude of inhibition of cAMP accumulation presented in figure 3 is incorrect and is more accurately reflected in the levels of cAMP inhibition shown in figure 4, which are follow-up experiments to those shown in figure 3.
These errors do not change the conclusion of the paper that the cloned kappa opioid receptor desensitizes after agonist treatment. This conclusion is supported by the three experiments presented in figure 4 and the results of multiple experiments presented in the other figures of the paper, as well as results described in the text of this paper.
Follow-up studies published from my laboratory (Blake et al., Differential agonist regulation of the human kappaopioid receptor—J Neurochem 68:1846–1852, 1997; Tallent et al., Differential regulation of the cloned kappa and mu opioid receptors—Neuroscience 85:873–885, 1998) have also reported that the cloned kappa receptor desensitizes.
The conclusions and results of Raynor et al. (1994) have been reproduced in numerous other published manuscripts by other laboratories. J. Zhu, L. Luo, G. Mao, B. Ashby and L. Liu-Chen (Agonist-induced desensitization and down-regulation of the humankappa opioid receptor expressed in Chinese hamster ovary cells—J Pharmacol Exp Ther 285:28–36, 1998) have recently reported in your journal that the clonedkappa opioid receptor desensitizes after agonist pretreatment. They specifically state in their paper “Our results onkappa opioid receptor desensitization, on the other hand, are consistent with those of Raynor et al. (1994) and Blakeet al. (1997).”
Ling et al. (Differential efficacies ofkappa agonists to induce homologous desensitization of humankappa opioid receptor—Neurosci Lett240:25–28, 1998), Kaneko et al.(Inhibition of Ca++ channel current by mu andkappa opioid receptors coexpressed in Xenopusoocytes: Desensitization dependence on Ca++ channelalpha1 subunits—Br J Pharmacol121:806–812, 1997) and Ma et al.(Kappa opioid receptor activates an inwardly rectifying K+ channel by a G protein-linked mechanism: Coexpression inXenopus oocytes—Mol Pharmacol47:1035–1040, 1995) have also reported results consistent with Raynor et al. (1994) that the clonedkappa receptor desensitizes.
Furthermore, numerous followup studies have reported that the native kappa opioid receptor desensitizes after agonist treatment. These include Jin et al. (Kappa opioid receptor tolerance in the guinea pig hippocampus—J Pharmacol Exp Ther 281:123–128, 1997), Appleyardet al. (Agonist-induced phosphorylation of thekappa opioid receptor—J Neurochem69:2405–2412, 1997), Sheng and Wong (Chronic U50,488H abolishes inositol 1,4,5-trisphosphate and intracellular Ca++ elevations by kappa opioid receptor in rat myocytes—Eur J Pharmacol 307:323–329, 1996) and Xia et al. (Effects of chronic U50,488H treatment on binding and mechanical responses of the rat hearts—J Pharmacol Exp Ther 268:930–934, 1994).
Finally, the results of our paper have been reproduced in a number of unpublished experiments performed in my laboratory since our paper was first submitted to the journal.
Terry Reisine, Ph.D.
- The American Society for Pharmacology and Experimental Therapeutics