Low levels of tension are effectively transmitted between TrA and the MLF or PLF. Via them, TrA may influence intersegmental movement.

We have developed methods that allow correlation of propulsive reflexes of the intestine with measurements of intraluminal pressure, fluid movement and spatio-temporal maps of intestinal wall movements for the first time in vivo. A segment of jejunum was cannulated and set up in a Trendelenburg recording system while remaining connected to the vascular and nerve supply of the anaesthetized rat. The resting intraluminal pressure in intact intestine was 2-4 mmHg. Hydrostatic pressures of 2, 4, 8 and 16 mmHg were imposed. At a baseline pressure of 4 mmHg, propulsive waves generated pressures of 9 +/- 1 mmHg, that progressed oral to anal at 2-5 mm s(-1). Individual propulsive waves propelled 0.8 +/- 0.4 mL of fluid. The frequency of propulsive waves increased with pressure, but peristaltic efficiency (mL per contraction) decreased with pressure increase between 4 and 16 mmHg. Atropine, as a bolus, transiently blocked peristalsis, but caused maintained block when infused. Hexamethonium blocked propulsive contractions. Inhibition of nitrergic transmission converted regular peristalsis to non-propulsive contractions. These studies demonstrate the utility of an adapted Trendelenburg method for quantitative investigation of motility and pharmacology of enteric reflexes in vivo.

We have used spatio-temporal maps derived from video images to investigate propagated contractions of the rat small intestine in vivo. The abdomen, including an exteriorized segment of jejunum, was housed in a humid chamber with a viewing window. Video records were converted to spatio-temporal maps of jejunal diameter changes. Intraluminal pressure and fluid outflow were measured. Contractions occupied 3.8 +/- 0.2 cm of intestine and propagated anally at 3.1 +/- 0.2 mm s(-1) when baseline pressure was 4 mmHg. Contractions at any one point lasted 8.7 +/- 0.6 s. Contractions often occurred in clusters; within cluster frequencies were 2.28 +/- 0.04 min(-1). Pressure waves, with amplitudes greater than about 9 mmHg, expelled fluid when the baseline pressure was 4 mmHg. In the presence of L-NAME, circular muscle contractions occurred at a high frequency, but they were not propagated. We conclude that video recording methods give good spatio-temporal resolution of intestinal movement when applied in vivo. They reveal neurally-mediated propulsive contractions, similar to those previously recorded from intestinal segments in vitro. The propagated contractions had speeds of propagation that were slower and frequencies of occurrence that were less than speeds and frequencies of slow waves in the rat small intestine.

We investigated the effects of the selective NK(3) tachykinin receptor antagonist, SB-235375, on noxious signalling from gut and skin and on intestinal motility in anaesthetized rats. We also measured penetrance into brain and spinal cord. Nociceptive responses in reaction to colorectal distension and skin pinch were assessed by recording the electromyogram (EMG) from the external oblique muscle (a visceromotor response). Motility was measured by recording intraluminal pressure waves during changes in baseline pressure in the jejunum. Colorectal compliance was assessed by measuring luminal pressure change during isovolumic distension. SB-235375 (20 mg kg(-1), by i.v. bolus) reduced the EMG response to colorectal distension by over 90%. The reduction was slow at onset, peaked at about 60 min, and lasted for over 2 h. Responses to noxious skin pinch were unchanged. Amplitudes of propulsive waves in the jejunum were slightly reduced, but their frequency of occurrence was unchanged. SB-235375 decreased colorectal compliance by 5-10%. There was undetectable penetration of i.v. SB-235375 into brain or spinal cord. We conclude that SB-235375 acts peripherally to substantially reduce nociceptive signalling from colorectum without affecting noxious signalling from skin and with little effect on intestinal motility.

Distension of the intestine is commonly used to elicit reflex responses at other sites in the gastrointestinal tract, and also to evaluate pain of intestinal origin. The sensory neurones, that initiate the reflexes or pain responses, react to the forces generated in the wall of the intestine. Thus, the responses of the intestine at the site of distension, particularly changes in contractile activity, influence the signals from the gut. In the present work we have analysed the relationship between distension and pressure changes in the jejunum of the rat, in vivo. Isovolumic distension for 5 min caused an initial pressure increase which declined quickly in the first 30 s, and then declined more slowly. Phasic pressure increases were superimposed on the baseline pressure change. Hexamethonium blocked the phasic pressure increases, whereas the initial rapid and subsequent slower pressure decline during distension persisted. Inhibition of nitric oxide synthase (NOS) increased intraluminal pressure and caused increased frequency and irregularity of phasic pressure increases. However, the decline in jejunal pressure during distension was not changed by inhibition of NOS. The pressure decline during isovolumic distension was similar whether saline or paraffin oil were used to distend the intestine, indicating that the decline was not due to increased hydrostatic pressure causing water and electrolyte to cross the mucosal epithelium from the lumen to the intestinal interstitium. Hyoscine had no significant effect on the pressure profile when the intestine was distended. However, when the systemic or the local circulation of the jejunum was infused with nicardipine, the pressure that was achieved during isovolumic distension was less, although the rate of change in pressure during the slow decline was similar. It is concluded that distension evokes phasic pressure increases in the jejunum, that are nerve-mediated, and increases the tension in the wall through a stretch-activated increase in contractile force generated by the circular muscle. The decline in pressure during maintained distension is primarily a consequence of visco-elastic properties of the wall of the intestine.

Noxious stimuli that are applied to different somatic sites interact; often one stimulus diminishes the sensation elicited from another site. By contrast, inhibitory interactions between visceral stimuli are not well documented. We investigated the interaction between the effects of noxious distension of the colorectum and noxious stimuli applied to the jejunum, in the rat. Colorectal distension elicited a visceromotor reflex, which was quantified using electromyographic (EMG) recordings from the external oblique muscle of the upper abdomen. The same motor units were activated when a strong pinch was applied to the flank skin. Distension of the jejunum did not provoke an EMG response at this site, but when it was applied during colorectal distension it blocked the EMG response. Jejunal distension also inhibited the response to noxious skin pinch. The inhibition of the visceromotor response to colorectal distension was prevented by local application of tetrodotoxin to the jejunum, and was markedly reduced when nicardipine was infused into the local jejunal circulation. Chronic sub-diaphragmatic vagotomy had no effect on the colorectal distension-induced EMG activity or its inhibition by jejunal distension. The nicotinic antagonist hexamethonium suppressed phasic contractile activity in the jejunum, had only a small effect on the inhibition of visceromotor response by jejunal distension. It is concluded that signals that arise from skin pinch and colorectal distension converge in the central nervous system with pathways that are activated by jejunal spinal afferents; the jejunal signals strongly inhibit the abdominal motor activity evoked by noxious stimuli.

Antagonists of NMDA receptors can inhibit both the transmission of pain signals from the intestine and enteric reflexes. However, it is unknown whether doses of the NMDA antagonist, ketamine, that are used in anaesthetic mixtures suppress motility reflexes and visceromotor responses (VMRs). In fact, whether intestinal motility is affected by NMDA receptor blockers in vivo has been little investigated. We studied the effects of ketamine and memantine, administered intravenously or intrathecally. Rats were maintained under alpha-chloralose plus xylazine or pentobarbitone anaesthesia; VMR and jejunal motility were measured. Under alpha-chloralose/xylazine anaesthesia, i.v. ketamine inhibited VMRs at 6 mg kg h(-1), but not at 3 mg kg h(-1). It did not inhibit propulsive reflexes in the jejunum at 10 mg kg h(-1), but reduced them by 30% at 20 mg kg h(-1). Under alpha-chloralose/pentobarbitone anaesthesia, i.v. ketamine reduced propulsive reflexes at 40 mg kg h(-1) and VMR at 10 mg kg h(-1). Memantine inhibited VMRs at 20 mg kg h(-1) and propulsion at 2 mg kg h(-1). Ketamine and memantine, intrathecally, prevented VMRs, but not jejunal propulsion. We conclude that peripherally administered ketamine reduces both VMR and motility reflexes, but not at doses used in anaesthetic mixes (1.8-2.4 mg kg h(-1)). Effects on motility reflexes are likely to be due to non-NMDA receptor actions, possibly on nicotinic receptors.

IntroductionThe time burden of managing relapsing remitting multiple sclerosis (RRMS) for patients and healthcare staff is not well quantified despite its importance in treatment choice. Of interest were three higher efficacy RRMS therapies, cladribine tablets, alemtuzumab, and fingolimod because of their different modes of administration. Time and motion (T and M) surveys have previously been used to quantify time burden by asking respondents about duration of treatment administration. The objective is to determine the time taken by patients, nurses, neurologist and other specialists to treat RRMS with cladribine tablets, alemtuzumab and fingolimod using purposely developed T and M surveys.MethodsWe created two T and M surveys, one for neurologists and nurses, and another for patients. Surveys were informed by product information documents, validated by an MS nurse, and completed by telephone with patients (n=3), neurologists (n=3), and nurses (n=8) from eight MS clinics.ResultsThe overall mean time spent on treatment with cladribine tablets, fingolimod, and alemtuzumab extrapolated over 4 years was 25±3, 62±6, and 189±18 hours (p<0.0001, 1-way ANOVA, repeated measures). Neurologists’ overall time spent also favoured cladribine tablets (2.3±0.7 hours) over alemtuzumab (9.5±1.8 hours) and fingolimod (2.9±0.7 hours), (overall p=0.001). Similar results were found for nurses and patients, with the largest difference between therapies (favouring cladribine tablets) recorded for patients.ConclusionCladribine tablets were associated with a significantly lower overall time taken to treat RRMS compared to fingolimod and alemtuzumab. This warrants further research to determine if cladribine tablets could (a) increase productivity for doctors and nurses, and (b) improve patient quality of life by reducing the burden of managing their disease.