Abstract
A single administration of the κ opioid receptor (KOR) antagonist, norbinaltorphimine (norBNI), produces long-term reduction in KOR function in heterologous expression systems and brain that is mediated by activation of c-Jun N-terminal kinase (JNK). In this study, we examined the long-term effects of norBNI on adult rat peripheral sensory neurons in vivo and ex vivo. Following a single intraplantar (i.pl.) injection of norBNI into the hind paw, peripheral KOR-mediated antinociception in the ipsilateral, but not the contralateral, hindpaw was abolished for at least 9 days. By contrast, the antinociceptive response to mu and delta opioid receptor agonists was unaltered. The long-term inhibitory effect on antinociception produced by pretreatment with norBNI required occupancy of peripheral KOR and was completely blocked by i.pl. injection of the JNK inhibitor, SP600125. In cultures of peripheral sensory neurons, norBNI activated JNK for at least 30 minutes. Furthermore, norBNI blocked KOR-mediated inhibition of adenylyl cyclase activity measured 24 hours later in a JNK-dependent manner, but did not block activation of extracellular signal-regulated kinase (ERK). The long-term inhibitory effect of norBNI on KOR function in vivo and ex vivo was blocked by inhibitors of mRNA translation, cycloheximide and rapamycin. These data suggest that in peripheral sensory neurons norBNI is a KOR-biased ligand for activation of JNK signaling, resulting in long-term blockade of some (antinociception, inhibition of adenylyl cyclase activity), but not all (ERK), KOR signaling. Importantly, norBNI elicits de novo protein synthesis in sensory neuron terminals that produces selective long-term regulation of KOR.
Footnotes
- Received May 15, 2016.
- Accepted September 2, 2016.
This work was supported by National Institutes of Health Public Health Service [Grant R01 GM 106035]; National Institutes of Health National Institute of Dental and Craniofacial Research (COSTAR) [Training Grant T32DE14318 to B.A.J.]; and National Institutes of Health National Institute on Drug Abuse [Grant T32 DA 031115 to L.C.S.]. R.J.J. was supported in part by the Translational Science Training program at University of Texas Health Science Center at San Antonio [TST128233].
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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