Mechanisms of long‐term regulation of peripheral kappa opioid receptor function by the antagonist, norBNI (659.4)

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KOR is known to regulate cellular signaling cascades including c‐Jun N‐terminal Kinase (JNK). We have found that norBNI, a prototypical KOR “antagonist”, has “agonist” activity towards JNK, leading to long‐term reduction in some aspects of KOR function in peripheral pain‐sensing neurons. Using a rodent behavioral model of nociception, we have found that KOR‐mediated peripheral antinociception is abolished 2 and 7 days following a single intraplantar injection of norBNI. This effect was blocked by pre‐injection of a selective JNK inhibitor, SP600125. Treatment of pain‐sensing neurons in culture with norBNI for 1h, followed by washing, eliminated KOR‐mediated inhibition of adenylyl cyclase, measured 24h later, which was blocked by SP600125. However, KOR‐mediated activation of extracellular signal‐regulated kinase (ERK) was unaffected by norBNI treatment.Since JNK is a well‐known activator of transcription factors, ultimately leading to protein synthesis, we sought to determine if protein synthesis is required for the long‐term effects of norBNI. Prior treatment with the protein synthesis inhibitor, cycloheximide, eliminated effects of norBNI, suggesting that increased synthesis of an unknown protein leads to prolonged reduction in some KOR‐mediated responses. These data provide strong evidence that norBNI is a protean ligand which has powerful capacity to regulate peripheral KOR function.Grant Funding Source: Supported by: DA024865, T32DA031115, TST128233/151325