This study determined the antinociceptive effects of morphine
and morphine-6-
O-sulfate (M6S) in both normal
and diabetic rats,
and evaluated the comparative role of
mu-
opioid receptors (
mu-ORs)
and delta-
opioid receptors (
delta-ORs) in the antinociceptive action of these
opioids.
In vitro characterization of
mu-OR
and delta-OR-mediated signaling by M6S
and morphine in stably transfected Chinese hamster ovary (CHO-K1) cells showed that M6S exhibited a 6-fold higher affinity for
delta-ORs
and modulated G-protein
and adenylyl cyclase activity via
delta-ORs more potently than morphine. Interestingly, while morphine acted as a full agonist at
delta-ORs in both functional assays examined, M6S exhibited either partial or full agonist activity for modulation of G-protein or adenylyl cyclase activity, respectively. Molecular docking studies indicated that M6S but not morphine binds equally well at the lig
and binding site of both
mu-
and delta-ORs.
In vivo analgesic effects of M6S
and morphine in both normal
and streptozotocin-induced diabetic Sprague-Dawley rats utilizing the hot water tail flick latency test showed that M6S produced more potent antinociception than morphine in both normal rats
and diabetic rats. This difference in potency was abrogated following antagonism of
delta- but not
mu- or kappa (kappa-ORs)
opioid receptors. During 9 days of chronic treatment, tolerance developed to morphine-treated but not to M6S-treated rats. Rats that developed tolerance to morphine still remained responsive to M6S. Collectively, this study demonstrates that M6S is a potent
and efficacious
mu/
delta opioid analgesic with a delayed tolerance profile when compared to morphine in both normal
and diabetic rats.
Perspective: This study demonstrates that M6S acts at both mu- and delta-ORs, and adds to the growing evidence that the use of mixed mu/delta opioid agonists in pain treatment may have clinical benefit.