Russell J. Sheldon

Gastrointestinal motor effects of corticotropin-releasing factor in mice.

The present investigation examined the effects of centrally and peripherally administered corticotropin-releasing factor on gastric emptying and gastrointestinal transit in mice. Corticotropin-releasing factor, given either intracerebroventricularly or intrathecally, caused a dose-dependent inhibition of gastric emptyping and gastrointestinal transit. Intravenous or intraperitoneal administration of corticotropin-releasing factor, while 5- to 7-fold less potent than after central injection, produced an equivalent level of effect. alpha-Helical corticotropin-releasing factor, a corticotropin-releasing factor receptor antagonist, blocked the effects of intracerebroventricularly administered corticotropin-releasing factor when the antagonist was given concurrently by the intracerebroventricular, but not by the intraperitoneal, route. Conversely, corticotropin-releasing factor, when given peripherally, was antagonized equally well by intracerebroventricular or intraperitoneal administration of the antagonist. The inhibition of gastric emptying induced by corticotropin-releasing factor was reduced by pretreatment with the ganglionic blocking agent, chlorisondamine, and in adrenalectomized mice, but this effect was not antagonized by naloxone. These findings provide evidence for an action of corticotropin-releasing factor within the central nervous system, as well as a peripheral site of action, to inhibit gastric emptying in the mouse. The gastrointestinal motor effects of corticotropin-releasing factor are not mediated through opioid mechanisms although their full expression may require intact autonomic innervation and adrenal function.

Sites of Clonidine Action to Inhibit Gut Propulsion in Mice: Demonstration of a Central Component

The role of central (supraspinal and spinal) and peripheral alpha-adrenoceptors in the regulation of gastrointestinal propulsion in the mouse was studied using clonidine, an alpha 2-adrenoceptor agonist. Clonidine produced a dose-dependent inhibition of propulsion when given intracerebroventricularly, intrathecally, or subcutaneously, but was most potent when given intracerebroventricularly. The antitransit effects of centrally given clonidine were antagonized by intracerebroventricular (i.c.v.) yohimbine, but higher doses were required when this antagonist was given peripherally. Whereas i.c.v. and s.c. administration of clonidine were effective in inhibiting gut transit in spinally transected mice, intrathecal (i.th.) administration of this agonist was not. A supraspinal site of clonidine action is suggested based upon (a) the higher central to peripheral potency of clonidine; (b) the greater potency of i.c.v., compared with s.c., administration of yohimbine in blocking i.c.v. clonidine; (c) the lack of effect of i.th. administration of clonidine in spinally transected mice; and (d) the reduced potency of i.c.v., but not s.c., administration of clonidine in spinally transected mice. Additionally, a peripheral site of clonidine action is suggested by (a) the lower potency of i.c.v. yohimbine in blocking s.c., compared with i.c.v., clonidine; (b) the lower potency of i.c.v. yohimbine in blocking i.c.v. clonidine in transected mice (compared with normal mice); (c) the equal potency of s.c. clonidine in slowing propulsion in normal and spinally transected mice; and (d) the equal potency of i.c.v. yohimbine in blocking s.c. clonidine in normal and spinally transected mice. These data in mice would thus support the concept that normal (peripheral) therapeutic administration of clonidine would affect gut motor function by interactions within the brain and directly at the level of the gut.

U50,488H differentially antagonizes the bladder effects of μ agonists at spinal sites

The mu antagonist property of the kappa agonist U50,488H was studied at the spinal level, using motility of the rat urinary bladder as an endpoint in vivo. Intrathecal (i.th.) administration of the mu agonists [D-Ala2,NMePhe4,Gly-ol]enkephalin (DAGO), [N-MePhe3,D-Pro4]enkephalin (PL017), morphine and normorphine, as well as the delta agonist [D-Pen2,D-Pen5]enkephalin (DPDPE), resulted in an equieffective inhibition of volume-initiated contractions of the urinary bladder. In contrast, i.th. administration of U50,488H, a highly selective kappa agonist, had no effect on bladder motility. Pretreatment of rats with i.th. U50,488H prior to agonist administration, blocked the suppression of spontaneous bladder activity induced by equieffective i.th. does of morphine and normorphine, but failed to alter the inhibitory effect of the mu agonists DAGO and PL017, or that of the delta agonist DPDPE. The finding that U50,488H differentially antagonized the identical bladder effects of several mu agonists suggests the presence of mu receptor subtypes (mu isoreceptors) in the rat spinal cord, which may be involved in the regulation of bladder function.

A comparison of the central gastrointestinal antitransit effects of morphine and bombesin in the mouse

The gastrointestinal motor effects of centrally-given morphine and bombesin were compared in mice. Both compounds produced a dose-related decrease in the propulsion of a marker along the gut when given by the intracerebroventricular (i.c.v.) or intrathecal (i.th.) routes. Co-administration of the same compound by both routes was found to produce a marked increase in potency for morphine, but only a slight increase in potency for bombesin. Isobolographic analysis of the gut effects of these compounds revealed a multiplicative brain-spinal cord interaction for morphine, but an additive interaction for bombesin. These results are consistent with the interpretation that morphine can act at either the level of the brain or the spinal cord, activating independent pathways which ultimately converge to alter gut propulsion. In contrast, spinal bombesin requires communication to supraspinal sites in order for its gut effects to occur, suggesting activation of a common outflow pathway from the central nervous system.