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, 523 Pt 2 (Pt 2), 403-11

P2X Purinoceptor-Induced Sensitization of Ferret Vagal Mechanoreceptors in Oesophageal Inflammation

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P2X Purinoceptor-Induced Sensitization of Ferret Vagal Mechanoreceptors in Oesophageal Inflammation

A J Page et al. J Physiol.

Abstract

1. Using an in vitro single unit recording technique we studied the changes in mechanical and chemical sensitivity of vagal afferent fibres in acute oesophagitis, with particular attention to inflammatory products such as purines. 2. Histologically verified oesophagitis was induced by oesophageal perfusion of 1 mg ml-1 pepsin in 150 mM HCl in anaesthetized ferrets for 30 min on two consecutive days. Controls were infused with 154 mM NaCl. 3. The number of action potentials evoked in oesophageal mucosal afferents by mucosal stroking with calibrated von Frey hairs (10-1000 mg) was stimulus dependent. In oesophagitis responsiveness was reduced across the range of stimuli compared with controls. 4. Topical application of the P2X purinoceptor agonist alphabeta-methylene ATP had no direct excitatory effect on afferents. In oesophagitis, but not in controls, there was a significant increase in responses to stroking with von Frey hairs during superfusion with alphabeta-methylene ATP (1 microM). 5. Mucosal afferents responded directly to one or more chemical stimuli: 26 % (5/19 afferents) responded in controls, and 47 % (7/15 afferents) in oesophagitis. There were no differences in responsiveness to bradykinin (1 microM), prostaglandin E2 (100 microM), 5-hydroxytryptamine (100 microM), capsaicin (1 mM) or hydrochloric acid (150 mM) between control and oesophagitis groups. 6. We conclude that a sensitizing effect of a P2X purinoceptor agonist on mechanosensory function is induced in oesophagitis. This effect is offset by a decrease in basal mechanosensitivity.

Figures

Figure 1
Figure 1. Protocols
Diagrammatic representation of the protocols followed for induction of acute oesophagitis or for control treatment. The procedures were carried out under general anaesthetic and were undertaken on consecutive days as shown.
Figure 2
Figure 2. Distal oesophageal tissue
Haematoxylin and eosin-stained transverse sections of distal oesophageal tissue from saline-perfused control (A) and acid-pepsin treated ferrets (B–D). B, complete shedding around a focal lesion (arrow) and areas of denuded epithelium (A and B: bar = 1 mm). C, higher magnification of lesion, with evidence of inflammatory cell infiltration (arrow) and basal cell hyperplasia (bar = 100 μm). D, inflammatory cell accumulation (arrow; bar = 50 μm).
Figure 3
Figure 3. Stimulus-response functions of mucosal afferents
Controls (▪; n = 32) and oesophagitis (▴; n = 26). The afferents recorded in oesophagitis showed significantly smaller numbers of evoked spikes per stroke than afferents in controls (two-way ANOVA, * P < 0.05).
Figure 4
Figure 4. Response of oesophageal mucosal afferents to mucosal stroking
Stimulus-response functions before (▪) and after (▴) exposure to the P2X receptor agonist αβ-methylene ATP in controls (A; n = 4, all A fibres) and oesophagitis (B; n = 8, all A fibres). Asterisk in B indicates that αβ-meATP significantly enhances the response to mucosal stroking in oesophagitis (two-way ANOVA, *P < 0.05). C, original recording of a mucosal afferent response to mucosal stroking with a 50 mg von Frey hair in oesophagitis in normal Krebs solution (i), 20 min after perfusion of αβ-methylene ATP (1 μM) (ii), and 20 min after reintroduction of normal Krebs solution (iii). Inset (iv) shows superimposed action potentials on a fast time base recorded at each stage described above (a-i, b-ii, c-iii), indicating that recordings were from the same single unit.
Figure 5
Figure 5. Responses to applied chemicals
Representative oesophageal mucosal receptor responses to 5-hydroxytryptamine (5-HT, 100 μM; A), bradykinin (1 μM; B), prostaglandin E2 (100 μM; C), hydrochloric acid (150 mM; D) and capsaicin (1 mM; E) in oesophagitis. The top trace for each section is spike frequency and the bottom trace is the raw recording of electrical activity. The responses shown are not all from the same fibre. Stimuli were left in contact with the receptive field for several minutes to allow full penetration of the mucosal epithelium. In A and E, more than one fibre was active on the strand being recorded. Individual units were discriminated on the basis of waveform. In B–D, the only active fibre is the one under investigation. In C–E a brief burst of firing is initially evoked before the response to chemicals which must have been caused by the mechanical effect of the solution being pipetted into the ring around the receptive field, because a similar initial burst was seen upon application of saline (not shown).

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