No abstract

P2X receptors are a family of ligand-gated ion channels responsive to ATP. Seven subtypes have been identified which form homo-multimeric or hetero-multimeric pores. P2X3 receptors are selectively expressed predominantly on small-diameter nociceptive sensory neurones in the dorsal root, trigeminal and nodose ganglia, particularly the non-peptidergic subpopulations labelled with the lectin IB4. P2X2/3 labelling is also present in inner lamina II of the spinal cord and in sensory nerve projections to skin and viscera, but few receptors are present in skeletal muscle. P2X3 receptors are down-regulated after peripheral nerve injury and their expression can be regulated by glial cell-derived neurotrophic factor. P2X receptor activation of sensory neurones has been demonstrated in in vivo pain models, including the rat hindpaw and knee-joint preparations, as well as in inflammatory models. P2X4 and/or P2X6 receptors in the CNS also seem to be involved in pain pathways. Non-nociceptive P2 receptors on sensory nerves are present in muscle and on sensory endings in the heart and lung that initiate reflex activity involving vagal afferent and efferent nerve fibres. The sources of ATP involved in nociception and non-nociceptive sensory nerve stimulation are discussed as well as a novel hypothesis about purinergic mechanosensory transduction.

SUMMARY1. The inhibitory innervation of the taenia of the guinea-pig caecum has been studied, after blocking the responses to stimulation of excitatory cholinergic nerves with atropine.2. Stimulation of the perivascular nerves supplying the taenia caused relaxations. These nerves had properties which were typical of sympathetic post-ganglionic adrenergic nerves. The relaxations caused by stimulation were maximal at frequencies of stimulation above 30 pulses/sec and they were abolished by bretylium, guanethidine and l,l-dimethyl-4-phenylpiperazinium iodide (DMPP).3. The taenia is also innervated by intramural inhibitory nerves with their cell bodies in Auerbach's plexus. These nerves can be excited by electrical stimulation ofthe taenia or by the application ofganglion-stimulating drugs.4. The intramural inhibitory nerves have different properties from sympathetic adrenergic nerves. Relaxations in response to stimulation were maximal with frequencies of stimulation of about 5 pulses/sec and they were not blocked by bretylium, guanethidine or DMPP.5. Preganglionic cholinergic fibres in the caecal wall make synaptic connexions with the intramural inhibitory neurones.6. The role of the intramural inhibitory neurones in intestinal activity and their possible connexions with the central nervous system have been discussed.

Distension of the perfused guinea pig ureter at pressures from 20 to 700 cmH(2)O increased the amount of ATP released from the epithelium in a pressure-dependent manner. During basal perfusion (40 microl/min), the perfusate contained 10 pmol/ml ATP; this increased 10- to 50-fold at various distending pressures. ATP was released from epithelial cells during distension as mechanical removal of the urothelium blocked release. No lactate dehydrogenase was detected in the perfusate, and scanning electron microscopy confirmed an intact urothelium after distension. ATP was not released due to the activation of stretch-activated channels, as gadolinium (10 microM) failed to affect ATP release. Glibenclamide (10 microM), known to inhibit two members of the ATP-binding cassette (ABC) protein family, did not affect ATP release after distension; nor did verapamil (10 microM). In contrast, both monensin (100 microM) and brefeldin A (10 microM), which interfere with vesicular formation or trafficking, inhibited distension-evoked ATP release, which was Ca(2+)-dependent. This suggests that ATP release from the ureter epithelium might be mediated by vesicular exocytosis. The role of ATP released by distension of hollow visceral organs is discussed in relation to the concept of purinergic mechanosensory transductions, with special reference to nociception and the activation of P2X(3) receptors on the subepithelial sensory nerves.