The effects of daikenchuto (DKT) on propulsive motility in the colon

Abstract

Background: The purpose of this study is to examine the use of daikenchuto (DKT), a traditional Japanese medicine, as a potential treatment for opiate-induced slowing of intestinal transit in an isolated guinea pig colon model of motility.

Methods: Isolated segments of distal guinea pig colon were mounted in a perfusion chamber and imaged with a digital video camera interfaced with a computer. Fecal pellets were inserted into the oral end of the colonic segment and the rates of propulsive motility over a 3 to 4 cm segment of colon were determined in the presence and absence of test compounds. In addition, intracellular recordings were obtained from intact circular muscle, and the responsiveness of inhibitory and excitatory junction potentials to DKT was evaluated.

Results: The addition of D-Ala2, N-Me-Phe4, Gly-ol5 (DAMGO), a selective μ-receptor agonist, caused a concentration dependent decrease in colon motility. Naloxone did not affect basal activity, but partially restored motility in the DAMGO treated preparations. DKT (1 × 10(-4)-3 × 10(-4)g/mL) also reversed the inhibitory effect of DAMGO treated colon in a concentration dependent manner. At higher concentrations (1 × 10(-3)-3 × 10(-3)g/mL), however, this effect was lost. Motility slowed even further when naloxone and DKT were combined with noticeable disruptions in spatiotemporal patterns. Interestingly, when added alone, DKT resulted in reverse peristalsis of the pellet. In electrophysiologic studies DKT inhibited both excitatory and inhibitory junction potentials.

Conclusions: DKT appears to be as effective as naloxone in restoring motility in DAMGO treated colon. These two agents, however, do not appear to have an additive effect. When used on untreated colon segments, DKT appears to cause disruptions in the intrinsic reflex circuit of the gut resulting in a disruption of neuromuscular communication.

Figure 1

Addition of the selective μ-receptor agonist, DAMGO (D-Ala2, N-Me-Phe4, Gly-ol5), reduced spontaneous neurogenic motility (not shown) and the rate of fecal pellet propulsion in isolated segments of the guinea pig distal colon. (n=5 colons at each concentration)

Figure 2

The non-selective opioid receptor antagonist, naloxone partially restored intestinal motility in the DAMGO-treated isolated guinea-pig distal colon.

Figure 3

Naloxone by itself did not affect the rate of pellet propulsion in the isolated guinea-pig distal colon. This indicates that endogenous opioids do not typically contribute to peristalsis in the guinea pig distal colon.

Figure 4

TU-100 caused a concentration-dependent reversal of the inhibitory effect of DAMGO on the rate of fecal pellet propulsion in the guinea pig distal colon.

Figure 5

Spatiotemporal maps showing pellet motility in a segment of guinea pig colon after the addition of naloxone to a bath containing DAMGO plus DKT. Combined application resulted in disrupted motor patterns of motility that included halted motility 5a or episodic periods of reverse peristalsis.5b.

Figure 6

Spatiotemporal map showing pellet motility in a segment of guinea pig colon in the presence on DKT alone.

Figure 7

Intracellular recordings obtained from smooth muscle cells. A) A typical tracing of spontaneous activity neuromuscular in an isolated segment of colon placed in a control bath. B) Spontaneous junction potential activity decreased when 3×10-4 g/ml of DKT was added to bath. C) Inhibitory junction potentials elicited by a depolarizing current to the oral end of an untreated isolated colon segment. D) Same inhibitory junction potentials blocked in the presence of DKT. E) Excitatory junction potentials elicited by a depolarizing current to the anal end of an untreated isolated colon segment. F) Excitatory junction potentials eliminated in the presence of DKT.