Peripheral micro-
opioid receptors (MOR) have emerged as important components of inhibitory nociceptive pathways. Here, the antinociceptive effects of MOR agonists, the 6beta-glycine derivative of
14-O-methyloxymorphone (HS-731),
DAMGO and
morphine were evaluated in a mouse model of
visceral pain. The abdominal
acetic acid-induced writhing test was used to examine the peripheral, preemptive antinociceptive
opioid action on visceral nociception.
HS-731 administered subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) dose-dependently and completely inhibited writhing, being 24-598-fold more potent, depending on the administration route, than two selective MOR agonists, the
enkephalin analogue [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]
enkephalin (
DAMGO) and
morphine. A longer duration of action (2-3 h) was induced by
HS-731 given before
acetic acid, while shorter effect was produced by
morphine (30-60 min) and
DAMGO (30-45 min). The antinociceptive effects of systemic
opioids were reversed by the s.c.
opioid antagonist,
naloxone. Blocking of central MOR by the selective MOR antagonist D-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH(2) (
CTAP, i.c.v.) resulted in a significant reduction of antinociception of s.c.
morphine, whereas it completely failed to antagonize the effects of systemic
HS-731 or
DAMGO. In in vitro studies,
HS-731 and
DAMGO, but not
morphine showed high intrinsic efficacy,
naltrexone-sensitive agonist effect at MOR of the rat vas deferens. These data demonstrate that selective activation of peripheral MOR by systemic s.c.
HS-731 or
DAMGO produces potent peripheral, preemptive visceral antinociception, while
morphine's effects are mediated primarily through central mechanisms. Our findings support the role of peripheral MOR in the pathology of
pain states involving sensitization of peripheral nociceptors.