TY - JOUR
T1 - Antinociceptive effects of herkinorin, a MOP receptor agonist derived from salvinorin A in the formalin test in rats
T2 - New concepts in mu opioid receptor pharmacology: From a symposium on new concepts in mu-opioid pharmacology
AU - Lamb, Kenneth
AU - Tidgewell, Kevin
AU - Simpson, Denise S.
AU - Bohn, Laura M.
AU - Prisinzano, Thomas E.
PY - 2012/3/1
Y1 - 2012/3/1
N2 - Herkinorin is the first μ 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 β-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 antinociceptive 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.
AB - Herkinorin is the first μ 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 β-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 antinociceptive 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.
KW - Formalin
KW - Herkinorin
KW - MOP receptors
KW - Morphine
KW - Tolerance
KW - β-Arrestin-2
UR - http://www.scopus.com/inward/record.url?scp=84857142520&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84857142520&partnerID=8YFLogxK
U2 - 10.1016/j.drugalcdep.2011.10.026
DO - 10.1016/j.drugalcdep.2011.10.026
M3 - Article
C2 - 22119134
AN - SCOPUS:84857142520
SN - 0376-8716
VL - 121
SP - 181
EP - 188
JO - Drug and Alcohol Dependence
JF - Drug and Alcohol Dependence
IS - 3
ER -
