In the present work, we have studied the effects of systemic morphine on the electrophysiological properties of ventromedial medulla (VMM) neurons in the awake, freely moving rat. By means of a chronically implanted single-unit recording device, a drug delivery catheter, and the use of controlled innocuous and noxious cutaneous stimuli, we were able to study precisely the spontaneous and evoked VMM neuronal activities. We have particularly focused our attention upon the VMM "multimodal, multireceptive" units, excited by non-noxious and noxious stimuli (VMM MULT ON), which we have already determined as the neuronal class potentially involved in nociceptive processes at VMM level. We found that morphine (3 mg/kg, i.v.) does not affect the spontaneous activity of these neurons whereas their responses to noxious heat are strongly attenuated (70%), over a prolonged period (about 2 hr) associated with an increase in the response latency. This action of morphine appears to be pharmacologically specific since it is dose dependent to some extent, and is reversed by 0.3 mg/kg of naloxone. In parallel with this pharmacological specificity, we have also demonstrated a preferential physiological effect since the response of the VMM MULT ON neurons to light touch application is not affected by morphine. This specificity is emphasized by the fact that morphine does not modify the activity of the other VMM neuronal groups such as the units unresponsive to any kind of peripheral stimuli, and does not reveal "new" neuronal classes such as those we have found in previous studies after barbiturate administration. The differential effect upon the noxious versus innocuous inputs of these units produced by the opiate reinforces their participation in nociceptive processing since similar effects have been reported in well-known nociceptive somatosensory structures such as the dorsal horn of the spinal cord. Furthermore, although the precise mechanisms of action have not yet been determined, the spinal projection of the VMM MULT ON neurons, previously demonstrated by our group, suggests their involvement in an opiate descending spinal control system of nociception. Although speculative, one can imagine either a direct facilitatory MULT ON spinal effect being attenuated by morphine (disfacilitation), or a morphine-induced disinhibition of inhibitory GABAergic neurons acting upon the MULT ON neurons.

In the present study, we precisely and automatically measured the withdrawal latency to noxious radiant heat application in unrestrained male rats and in human subjects of both sexes, by means of the "plantar test" apparatus (Ugo Basile Biological Apparatus). The infrared light stimulus of this tool was applied underneath the hindpaws of rats and the middle fingers of human subjects. With one right and one left stimulation every 10 min, we observed a decrease in latency over a 40-min testing period in rats; the latency reached a mean value of 5.08 +/- 0.25 sec after 40 min with a 36-W stimulus, which corresponded to 46.5 degrees C. In pilot experiments, also performed on rats, we showed that the opiate morphine (10 mg/kg, i.p.) produced remarkable increases of the withdrawal latency only in "naive" animals (i.e., ones that had never experienced the plantar test stimulus) and not in animals "habituated" to it. Among humans, we noted gender differences, such as less sensitivity to the infrared noxious radiant heat for women, particularly during the menstrual period. A difference from rats was that there was no significant latency modification along the 40-min testing period for either women or men, with a mean latency of 5.61 +/- 0.18 sec (47.5 degrees C) for the women and 4.39 +/- 0.10 sec (45.5 degrees C) for the men. These data confirm the reliability of the plantar test in rats, and demonstrate the possible use of an infrared source in human subjects as a noxious heat stimulus; the withdrawal reaction to this stimulus is emphasized as a good index of nociception in humans.

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The paper describes in vivo voltammetric detection of nitric oxide with carbon fibre microelectrodes at the lumbar spinal dorsal horn level of decerebrated-spinalized rats during peripheral noxious inflammatory processes. At the lumbar (L3-L4) dorsal horn level, a nitric oxide dependent peak of oxidation current (650 mV), remaining stable for up to 4h ((92 +/- 5)% of control) could be detected indicating that significant amounts of nitric oxide are produced continuously. Following subcutaneous injection in the hindpaw of 50 microl of 0.5% formalin the oxidation current rapidly increased ((115 +/- 5)% of control at 25 min) and reached (120 +/- 6)% of control 1h later. Subsequently the voltammograms stabilized for up to 90 min and decreased ((107 +/- 4)% at 124 min). After an injection in the hindpaw of 150 microl of 4% carrageenan, the voltammograms remained at control level for 1h and then the oxidation current increased continuously for up to 4h ((145 +/- 16)% of control at 240 min); such an increase was reversed by ketamine. In these two models of inflammation, the delay in onset and the duration of the increases in NO release within the dorsal horn relate, to some extent, to the time course of the peripheral inflammatory processes, since they are shorter after formalin than after carrageenan. The results provide a direct in vivo demonstration that the intercellular messenger nitric oxide participates in the transmission of noxious afferent messages within the dorsal horn of the spinal cord following peripheral inflammation.

In this study, we recorded the single-unit activity of the dorsal raphe nucleus (DRN) in rats tested first awake and, a few days later, anesthetized with sodium pentobarbital and recorded again. This was achieved by means of a small chronically implanted device supporting a 25 micron platinum-iridium wire as the recording electrode. In both the awake and anesthetized conditions, and in agreement with most of the studies performed at the DRN level, we found that a vast majority of the units, displaying small amplitude and long-duration action potentials, possessed a low level of spontaneous activity (0.2-4 Hz). Among these units, found in greater number under pentobarbital, it was possible to establish that this activity was regular or irregular, in accordance with the literature reports. However, as opposed to these studies, we determined that the 'regularity' was relative, only noticeable in more or less prolonged phases of activity. In particular, we never recorded the so-called 'clock-like' activity, largely reported as an unambiguous criterion for selecting the serotoninergic neurons. In both the awake and anesthetized conditions, the responses of the DRN neurons to peripheral mechanical innocuous and noxious stimulations were observed in only one-half of the units recorded and were weak in comparison to other results that we obtained at the nucleus raphe magnus level in previous studies. When present, these responses were excitation or inhibition, occurring during or after the stimulus application. These results question the direct involvement of the DRN in acute nociception.