Intrathecal morphine slows gastrointestinal transit in rats

Intrathecal (i.th.) (by direct lumbar puncture) and intraperitoneal (i.p.) administration of morphine (30-100 [mu]g/rat) caused a dose-related inhibition of gastrointestinal transit in the rat. Pretreatment with i.th. naloxone (5 [mu]g at -5 min) reversed the effects of i.th., but not i.p., morphine. These results suggest that the spinal cord appears to be a target site for the inhibitory effects of morphine on gastrointestinal transit in the rat.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25467/1/0000005.pd

Modulation of [mu]-mediated antinociception by [delta] agonists in the mouse: selective potentiation of morphine and normorphine by [D-Pen2, D-Pen5]enkephalin

The effect of the [delta]-selective agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) on the antinociception produced by intracerebroventricular (i.c.v.) administration of the [mu] agonists morphine, [D-Ala2, NMePhe4,Gly-ol5]enkephalin (DAGO), [NMePhe3,D-Pro4]morphiceptin (PLO17), [beta]-endorphin, phenazocine, etorphine and sufentanil was studied in mice. Only the antinociceptive effects of morphine and normorphine were modulated by i.c.v. coadministration of a dose of DPDPE which did not prodice any significant antinociception alone. Both the morphine and normorphine dose-response lines were displaced to the left in the presence of DPDPE. The [delta]-selective antagonist ICII74,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH) (where Aib is [alpha]-aminoisobutyric acid) blocked the modulation of morphine antinociception by DPDPE. ICI 174,864 alone failed to produce either a significant increase or decrease of morphine, phenazocine, etorphine or [beta]-endorphin antinociception. The results of the present study provide support for the hypothesis that the enkephalins may function to modulate antinociception produced at the [mu] receptor; such modulation may come about via the existence of an opioid [mu]-[delta] receptor complex. The [mu] receptors existing in such a complex may be selectively activated by morphine and normorphine, but not the other [mu] agonists studied here. Thus, the enkephalins may function both to directly initiate, as well as to modulate, some forms of supraspinal [mu] receptor-mediated antinociception.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27888/1/0000302.pd

Neurotrophic 3,9-Bis[(Alkylthio)Methyl]-and-Bis(Alkoxymethyl)-K-252a Derivatives

A series of 3,9-disubstituted [(alkylthio)methyl]- and (alkoxymethyl)- K-252a derivatives was synthesized with the aim of enhancing and separating the neurotrophic properties from the undesirable NGF (trk A kinase) and PKC inhibitory activities of K-252a. Data from this series reveal that substitution in the 3- and 9-positions of K-252a with these groups reduces trk A kinase inhibitory properties approximately 100- to \u3e500-fold while maintaining or in certain cases enhancing the neurotrophic activity. From this research, 3,9-bis[(ethylthio)methyl]-K-252a (8) was identified as a potent and selective neurotrophic agent in vitro as measured by enhancement of choline acetyltransferase activity in embryonic rat spinal cord and basal forebrain cultures. Compound 8 was found to have weak kinase inhibitory activity for trk A, protein kinase C, protein kinase A, and myosin light chain kinase. On the basis of the in vitro profile, 8 was evaluated in in vivo models suggestive of neurological diseases. Compound 8 was active in preventing degeneration of cholinergic neurons of the nucleus basalis magnocellularis (NBM) and reduced developmentally programmed cell death (PCD) of female rat spinal nucleus of the bulbocavernosus motoneurons and embryonic chick lumbar motoneurons