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Notes: Background and Aim: Gastric hypersensitivity to mechanical distension has been observed in functional dyspepsia, but no drug is available that specifically acts on gastric afferent pathways to decrease gastric nociception. The aim of this study was to assess the effect of fedotozine, a synthetic ligand for peripheral kappa receptors, on human gastric sensitivity. Methods: Twenty-seven healthy volunteers were randomized to receive either fedotozine (30 mg t.d.s.) or a placebo, for 7 days. On day 7, the effects of fedotozine were tested on discomfort threshold and gastric compliance during graded isobaric and isovolumic distensions. In 16 of these subjects, the effect of this drug was tested on somatic sensitivity. In 10 other healthy volunteers the effect of fedotozine on gastric distension-induced inhibition of the RIII reflex, a process closely related to visceral sensitivity, was also studied. Results: During isobaric distensions, the discomfort threshold was significantly higher in subjects on fedotozine than in those on placebo (14.4±0.92 vs. 12.0±1.13 mmHg; P=0.04). Compared to placebo, fedotozine did not modify gastric compliance and somatic sensitivity. Fedotozine also reduced the inhibition of the RIII reflex induced by gastric distension. Conclusion: Fedotozine decreases gastric sensitivity to distension by exerting specific action on gastric afferent pathways.

Notes: Summary Single unit responses to noxious and non-noxious somatic stimulation were investigated in the somatosensory (SmI) cortex of rats under halothane-nitrous oxide anaesthesia. Four categories of neurons were observed: (1) neurons driven by non-noxious cutaneous stimulation, (2) neurons driven by non-noxious deep stimulation, (3) neurons driven by noxious stimulation only (nociceptive specific neurons), (4) neurons driven by noxious as well as non-noxious stimulation (convergent or nociceptive non-specific neurons). The receptive fields of the neurons driven by contralateral cutaneous non-noxious stimulation were small. These neurons responded phasically to cutaneous stimulation in the majority of cases. Neurons driven by stimulation of deep receptors (e.g. joint movement) could also be recorded in the same part of SmI cortex. Neurons driven by noxious stimulation had large receptive fields and were often tonically driven by noxious stimulation. Convergent (or nociceptive non-specific) neurons could often be inhibited from body parts not included in their excitatory receptive field. Some neurons driven by noxious stimulation were able to encode stimulus parameters such as temperature of a hot water bath or surface of the skin area stimulated. The different categories of neurons defined above could be successively recorded during a given electrode penetration. Evidence for the somatotopic organization of the different categories of inputs was obtained. These results strongly suggest that the first somatosensory (SmI) neocortex is involved in nociception.

Notes: Summary The effects of oxapadol, a new non-narcotic analgesic, were tested in man using the electrically-induced nociceptive flexion reflex in the flexor muscles of the lower limb as an index of pain. The drug caused a significant increase in the threshold of the reflex whereas no change was noted with placebo.

Notes: Summary Single-unit recordings were made under moderate gaseous anaesthesia in the hindpaw representation area of the two primary somatosensory motor cortices (SmI) of rats (n = 58) rendered mononeuropathic by four loose ligatures placed around one common sciatic nerve 2–3 weeks beforehand. The rats exhibited clear hyperalgesia and allodynia from the paw with the ligated sciatic nerve, to both mechanical and thermal stimuli. From the tested neuronal population (n = 640), about the same proportion could be activated by somatic stimuli in each cortex: 165/362 (45%) in the cortex contralateral to the ligated sciatic nerve (Cc), 105/278 (37%) in the cortex ipsilateral to the ligated sciatic nerve (Ci). Neurones driven by light touch, exhibited RFs strictly contralateral to the recording sites. Their proportion and response characteristics were similar regardless of recording side. However, the number of neurones with RFs in the sciatic nerve territory was above 95% in the Ci, and was dramatically reduced to 43 % in the Cc. By contrast, the number of neurones with RFs supplied by the saphenous nerve reached 57% on this side. Although the RF size of all the neurones appeared roughly normal, there were fewer Cc than Ci neurones with RFs located on the paw itself and with RFs of extremely small size in the sciatic nerve territory. The proportion of neurones responding to a joint stimulus was significantly higher in the Cc than in the Ci. The neuronal responses to joint stimuli of the paw with the ligated sciatic nerve were significantly more sustained than those recorded in the Ci and elicited from the normal paw. The proportion of neurones driven by mechanical stimulation which gave rise to nociceptive reactions in freely moving animals, i.e. “nociceptive” neurones, was comparable in each cortex. However, half of the Cc neurones exhibited paroxysmal discharges occuring without intentional stimulation and of long duration (l min to several minutes). Only 66% of Cc but 93% of Ci “nociceptive” neurones were exclusively activated by pinch. The remaining Cc neurones were also activated by applying moderate pressure to the paw with the ligated nerve. Pinch responses from the paw with the ligated nerve were often more intense and of longer duration than responses elicited from the intact paw. The “nociceptive” Cc neurones were especially sensitive to thermal stimuli of 39–44° C when the stimuli were applied to the paw with the ligated nerve. They also responded vigorously to a 10° C stimulus applied to this paw. They were therefore, sensitive to thermal stimuli usually considered to be in the non-noxious range. In the SmI cortex opposite to the ligated sciatic nerve, there was no change in the proportion of somatosensory neurones, but a rearrangement of the various somatic inputs. Although reduced, there were consistent light tactile inputs from the damaged sciatic nerve giving rise to roughly normal neuronal responses, and simultaneously a noticeable increase in tactile signals from the saphenous nerve territory. There was also a significant increase in joint inputs from the paw with the ligated sciatic nerve. The possible functional role of such input rearrangement is discussed. The dramatic changes in the responses of “nociceptive” neurones to stimuli applied to the paw with the ligated sciatic nerve and the clear decrease in their activation threshold to mechanical and thermal stimuli could account for some of the abnormal pain-related behaviours that were exhibited. These data emphasize, again, that the primary sensory cortex is involved in nociceptive processing.

Notes: Summary The laminar and columnar organization of the rat SmI cortex was investigated under halothanenitrous oxide anaesthesia during microelectrode penetrations perpendicular to the cortical surface, using histological reconstruction of the electrode tracks. Neurons were studied in terms of receptive field properties (see companion paper) and laminar distribution. Neurons driven by non-noxious cutaneous stimulation and others by non-noxious deep stimulation, applied on contralateral receptive fields, could be recorded in the same penetration. Modality specific penetrations were observed in 48% of cases only. This finding suggests that there is little submodality segregation in the rat SmI cortex. Receptive fields successively observed in a given penetration were usually overlapping. “Modality-specific” columns were less often observed than “place-specific” columns during radial penetrations. Neurons driven by non-noxious stimulation as well as neurons driven by noxious stimulation could be recorded successively in the same penetration. Neurons driven by non-noxious cutaneous stimulation were found in layers II to V and were rare in layer VI. In contrast, nociceptive specific neurons were found almost exclusively in layers Vb and VI and convergent neurons in layer V. The size of the receptive fields was a function of the laminar position of the neurons: receptive fields were, on the average, small in layer IV, larger in layer II–III and V and even larger in layer VI. The somatotopic organization of the receptive fields of neurons driven by noxious stimulation was different from that of neurons driven by non-noxious stimulation. Such a difference was due in part to the larger size of the receptive fields of the neurons driven by noxious stimulation and also to their different topographical organization. These results provide new data concerning the functions of the rat SmI cortex. Namely they show that the cortical processing of somatic non-noxious and noxious inputs is based on laminar as well as columnar patterns of organization.