In the studies reported here, we have demonstrated that DKT partially reverses opiate-induced slowing of propulsive motility in the guinea pig distal colon. The extent of this effect is comparable in magnitude to that of the opioid receptor antagonist, naloxone. The inhibitory effects of opiates, such as morphine, and opiate analogs, such as DAMGO, are largely attributed to the suppression of neuronal excitability resulting in subsequent inhibition of neurotransmitter release from enteric excitatory and inhibitory musculomotor neurons.13
Experiments performed in guinea-pig myenteric plexus-longitudinal muscle preparations have demonstrated that exposure to opioids results in suppression of acetylcholine and substance P release. Since the primary input to longitudinal muscle is excitatory, the absence of these excitatory neurotransmitters results in inhibition of longitudinal muscle contraction.14,15
Unlike longitudinal muscle, the predominant neuromuscular input to the circular muscle layer is inhibitory. In a quiescent state, there is ongoing firing of inhibitory motor neurons resulting in relaxation of the circular muscle layer.16
This allows the bowel to relax and receive advancing intraluminal contents. In the presence of opioids and opioid analogs, however, the firing of these inhibitory motorneurons is suppressed thereby resulting in elevated contractile activity of this muscle layer. Taken together, the lack of longitudinal muscle contraction and the absence of circular muscle relaxation result in decreased propulsive motility.
Previous studies have suggested that DKT is able to overcome morphine-induced slowing of transit by causing moderate contraction of morphine-treated longitudinal muscle and relaxation of morphine-induced tonic contraction of circular muscle.12
The exact neuronal mechanism by which this occurs is unknown, but appears to be partly associated with stimulation of serotonin receptors and vanilloid receptors.12,17
The various constituents of DKT were not examined independently in these experiments, but previous experiments indicate that the active ingredient in DKT is the Sichuan pepper. Experiments performed on guinea pig colon revealed similar contractile effects between DKT and Sichuan pepper alone. Meanwhile, the Asian ginseng and ginger had no contractile effect.18
Clearly, clinical trials utilizing DKT are needed, but the results of these experiments suggest that DKT could potentially offer a therapeutic role in the management of opiate induced ileus. Unlike naloxone which blocks the opiate receptor and thereby negates any positive analgesic effect, DKT appears to have no alteration of the anti-nociceptive affect in mice.12
This would be of particular use in a post-operative setting where systemic opiates would be needed for analgesia.
When used in the absence of opiates, DKT was observed to cause disruptions in the intrinsic reflex circuit of the gut by interfering with neuromuscular transmission. This was first apparent by visualizing spontaneous contractile activity of the colonic segments and with our spatial-temporal maps. The isolated colon segment was observed to move erratically in the presence of DKT rather than contract rhythmically as it did in the absence of DKT. This interesting observation may also help explain why DKT has been useful for the prevention of adhesive bowel obstructions. One proposed mechanism by which post-operative adhesions form has to due with areas of bowel stasis. The theory suggests that areas of hypokinesis allow more time for scar tissue to form and adhere, thereby causing an obstruction. Such a theory is supported when one encounters a single adhesive band during laparotomy. Since DKT apparently causes hyperkinesis, it would seem reasonable that this increased motion would not allow sufficient time or stasis for adhesions to form.
From these experiments, it is clear that DKT is effective in overcoming the slowing of motility produced by the presence of opiates such as DAMGO. Furthermore, this amelioration seems to work by a mechanism that is different from that of opiate-receptor antagonists. When used in the absence of opiates, however, a very different result becomes apparent. Rather than accelerate motility or even produce no effect, DKT seemed to cause drastic disruptions in propulsive motor activity. It is unknown what effect, if any, these disruptions would have in human subjects. It would seem that further work needs to be done in order to understand the exact mechanism by which these disruptions occur. This could include examining how the individual ingredients of DKT influence both neuronal and muscle signal transmission. This, unfortunately is beyond the scope of this present study.
In summary, the results of this investigation suggest that DKT is as effective as naloxone in restoring motility in DAMGO treated guinea pig colon. The actions of these two agents, however, were not additive. These findings suggest that DKT might provide some benefit in the restoration of colonic motility in post-operative patients receiving opiate analgesic therapy and/or in patients requiring chronic opiate use.