期刊
DRUG AND ALCOHOL DEPENDENCE
卷 121, 期 3, 页码 181-188出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.drugalcdep.2011.10.026
关键词
MOP receptors; Herkinorin; beta-Arrestin-2; Morphine; Tolerance; Formalin
资金
- NIDA NIH HHS [R01 DA018151-01A2, K01 DA014600-01, R01 DA018860-01, K01 DA014600, R01 DA018151, R13 DA029347, R01 DA018860, R01 DA018151-05S1] Funding Source: Medline
Herkinorin is the first mu opioid (MOP) selective agonist derived from salvinorin A, a hallucinogenic natural product. Previous work has shown that, unlike other opioids, herkinorin does not promote the recruitment of beta-arrestin-2 to the MOP receptor and does not lead to receptor internalization. This paper presents the first in vivo evaluation of herkinorin's antinociceptive effects in rats, using the formalin test as a model of tonic inflammatory pain. Herkinorin was found to produce a dose-dependent decrease in the number of flinches evoked by formalin. These antinocicepdve effects were substantially blocked by pretreatment with the nonselective antagonist naloxone, indicating that the antinociception is mediated by opioid receptors. Contralateral administration of herkinorin did not attenuate the number of flinches evoked by formalin, indicating that its effects are peripherally restricted to the site of injection. Following chronic administration (5-day), herkinorin maintained antinociceptive efficacy in both phases of the formalin test. Furthermore, unlike morphine, herkinorin was still able to inhibit flinching in both phases of the formalin test in animals made tolerant to chronic systemic morphine treatment. Collectively, these results suggest that herkinorin may produce peripheral antinociception with decreased tolerance liability and thereby represents a promising template for the development of agents for the treatment of a variety of pain states. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
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