SUMMARY1. The contractile effect of substance P on the longitudinal muscle of the isolated guinea-pig small intestine and the desensitization of the muscle which occurs on prolonged exposure to the peptide have been investigated. All experiments were performed in the presence of atropine.2. The response to a substance P concentration which produced a nearly maximal effect was not sustained but faded rapidly. It was found that not elimination of substance P from the bath, but desensitization of the muscle to substance P was the main cause for the fading of contraction.3. Desensitization of the muscle to substance P only developed if the muscle was exposed to the peptide for a certain time. The degree of and the time needed for recovery from desensitization were directly related to concentration of substance P and contact time.4. Tetraethylammonium (3 mM), which reduces the membrane conductance for K+, enhanced the potency of substance P in contracting the muscle and reduced the fading of contraction. Noradrenaline (295 nM), which increases the K+ conductance, produced opposite effects.5. Lowering the extracellular Ca2+ concentration to one-tenth decreased the potency of substance P in contracting the muscle, accelerated the fading of contraction, and reduced the ability of the muscle to respond to a second addition of substance P after the response to the first addition had faded away.6. Concentrations of substance P (22 nM) and tetraethylammonium (30 mM), which produced nearly maximal contractions, slightly enhanced the efflux of 86Rb from pre-loaded muscle strips. Both substances, however, caused a sustained reduction of 86Rb efflux from strips depolarized by high [K+], the effect of substance P being smaller than that of tetraethylammonium. The effect of substance P and tetraethylammonium on 86Rb efflux appeared independent of the extracellular [Ca2+].7. On exposure of the muscle to substance P (22 nM) for 8 min the intracellular uptake of 46Ca was first decreased and then increased while the 45Ca influx was instantly enhanced by tetraethylammonium (30 mM) or K+ (108 mM). The delayed increase in 45Ca influx caused by substance P was also observed in muscle strips depolarized with high [K+].-P. HOLZER AND U. PETSCHE 8. Taken together, the results suggest that there are two mechanisms of action by which substance P causes contraction of intestinal smooth muscle: reduction of a K+ conductance and a mechanism dependent on the extracellular [Ca2+]. Circumstantial evidence indicates that desensitization of the muscle to substance P arises from a block in excitation-contraction coupling and the hypothesis has been put forward that fading of the contractile response and desensitization reflect depletion of a Ca2+ store which is operated by the substance P receptor.
Excitability of afferent C-fibres in a skin nerve was studied in 28 rats treated with capsaicin on day two of their lives (80 mg/kg, s.c.). At the age of 4-5 months they were subjected to experiments in which recordings were made from single C-fibre units of saphenous nerve. The effectivity of neonatal capsaicin treatment in blocking reactions to the irritating action of the toxin was evaluated with the wiping test. Five untreated rats served as controls. In capsaicin treated animals afferent cutaneous C-fibres were diminished by more than 50%. No significant change was found, however, in the spectrum of kinds of cutaneous receptors. In particular, the ratio between nociceptors responding to heat and mechanical stimuli (polymodal nociceptors, MH-units) and other C-fibre receptors, such as sensitive cold units was not changed significantly. Furthermore, in the animals neonatally treated with capsaicin conduction velocities of afferent C-fibres and thresholds to mechanical and thermal stimuli were not significantly altered. In both capsaicin treated and control samples, the spike conduction in most of the mechano- and heat sensitive C-nociceptors was blocked by acute topical application of this toxin to the nerve stem. It is concluded that part of the afferent C-fibres survived neonatal capsaicin treatment, even in those rats that showed complete intensitivity to the toxin in behavioural tests.
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