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.