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1.
Diffuse Noxious Inhibitory Controls (DNIC) were investigated in anaesthetized intact rats, with or without p-chlorophenylalanin (pCPA) pretreatment. Dorsal horn convergent neurones responding to both noxious and non-noxious stimuli applied to their excitatory receptive field located on the distal part of the hindlimb, were recorded in the lumbar spinal cord. These cells received Aα and C fibre inputs as shown by electrical stimulation of their receptive field.In control animals, the evoked responses to C fibre inputs coulb be strongly inhibited by various noxious stimuli applied to widespread areas of the body: the inhibitory effects induced by intraperitoneal administration of bradykinin, pinch applied to the tail or muzzle and noxious heat applied to the tail were of 77%, 87%, 83% and 61% respectively. Long-lasting post-effects were seen in most cases after cessation of the application of the conditioning stimulus.Pretreatment with pCPA (300 mg/kg, i.p., 3 days) resulted in a strong reduction of DNIC. The inhibitory effects induced by intraperitoneal administration of bradykinin, pinch applied to the tail or muzzle and noxious heat applied to the tail were reduced by 47%, 63%, 87% and 63%, respectively. The post-effects were also reduced both in terms of magnitude and duration.These results strongly suggest that serotonergic pathways are partially involved in  相似文献   

2.
K Taguchi  Y Suzuki 《Brain research》1992,583(1-2):150-154
The effects of cutaneous noxious heating and of systemic morphine on serotonergic activity in the spinal cord were examined in anesthetized rats. An oxidation current of 5-hydroxyindole signal was seen at 280-300 mV with differential normal pulse voltammetry. Noxious heat stimuli produced a mean signal increase over control values of 15.5 +/- 3.4% at 52 degrees C, and 7.2 +/- 5.5% at 45 degrees C. These increases lasted for 5-10 min. Non-noxious stimuli (37 degrees C) did not affect the 5-hydroxyindole signal. Morphine (0.5, 2.0 and 5.0 mg/kg, i.p.) in the absence of cutaneous stimulation did not change the signal significantly. Systemic morphine alone did not significantly modify the 5-hydroxytryptamine (5-HT) metabolism, as observed in in vivo voltammetry, in the spinal cord of anesthetized rat. However, a low dose of morphine (0.5 mg/kg, i.p.) attenuated the increase in the signal modified by noxious stimuli, and high doses (2.0 or 5.0 mg/kg, i.p.) enhanced it. Both effects of morphine were antagonized by naloxone (0.5 mg/kg, i.v.). It is likely that morphine with noxious stimuli modify the sensitivity of serotonergic descending inhibitory system. It is concluded that noxious heating of the skin increases the 5-HT metabolism in the spinal cord of anesthetized rats and that systemic administration of morphine modulates this 5-HT metabolism.  相似文献   

3.
The effect of exogenous opiates upon diffuse noxious inhibitory controls (DNIC) was investigated in intact anaesthetized rats. 58 convergent neurones, responding to both noxious and innocuous stimuli applied to their cutaneous receptive fields, were recorded at the lumbar level. These cells received A- and C-peripheral fibre inputs as shown by electrical stimulation of their receptive fields and were mainly located in the medial part of the dorsal horn.The immersion of the distal two-thirds of the tail in hot water (52 °C) induced strong inhibition of the responses to both A-(23%) and C-(69%) fibres. Post-effects of long duration were commonly observed after cessation of the conditioning stimulus.While systematic injection of morphine at a low dose-range (0.1–1 mg/kg) did not significantly affect the unconditioned responses, the DNIC-mediated inhibitions were profoundly altered.(a) DNIC of responses to C fibres were dose-dependently (P < 0.01) lifted by morphine: (b) the post-effects observed after cessation of conditioning stimuli were dose-dependently (P < 0.01) diminished; (c) DNIC of responses to A-fibre were similarly altered but this effect was less significant (P < 0.05); (d) DNIC of responses to sustained moderate pressure were greatly diminished by morphine (P < 0.01); and (e) these effects were specific since they were antagonized by the opiate antagonist, naloxone. In addition, they were shown to be stereospecific since while the dextrogyre stereoisomer, dextrorphan, was ineffective the levogyre derivative, levorphanol, induced a significant lifting of DNIC.It is concluded that morphine decreases the supraspinal inhibitory controls of dorsal horn convergent neurones, at least when these controls are triggered by noxious stimuli. Assuming that a basic somatosensory background activity (noise) is transmitted to higher centres by dorsal horn convergent neurones, and that the pain-signalling message is the contrast between the activity of the segmental pool of neurones induced by the noxious stimulus and the DNIC-mediated silence of the remaining neuronal population, it is proposed that, by a reduction in DNIC, low-dose morphine could restore the initial level of background activity, the final result being analgesia.  相似文献   

4.
Activity produced by direct microelectrophoretic application of glutamate onto 19 convergent neurones in trigeminal nucleus caudalis, was strongly depressed during and after the application of heterotopic noxious conditioning stimuli: noxious heat (52 °C) applied to the tail, noxious pinches applied to the tail or hindpaws and intraperitoneal injections of bradykinin produced mean reductions in activity of 80–90%. The same noxious conditioning stimuli had no effect on the activities of any of 5 noxious-only or 5-non-noxious-only neurones. These effects were similar to those previously reported to influence peripherally evoked activities of nucleus caudalis convergent neurones and which have been termed diffuse noxious inhibitory controls (DNIC). It is therefore proposed that DNIC act on nucleus caudalis convergent neurones by a final post-synaptic inhibitory mechanism involving hyperpolarisation of the neuronal membrane. Consistent with this hypothesis, it was also found that the noxious conditioning stimuli could restore firing of convergent neurones which had been excessively depolarized by large doses of glutamate.  相似文献   

5.
Electrical or chemical stimulation of the superior colliculus (SC) in rats produces orienting and defensive responses. Defensive behaviors are modulated by serotonin (5-hydroxytryptamine, 5-HT), and serotonergic fibers provide a dense innervation of the SC. Here, we examined the role of 5-HT in modulating the behavioral responses of rats elicited by electrical SC stimulation. Low-intensity (107+/-12 microA) stimulation of the SC elicited orienting head movements, while higher intensities (204+/-20 microA) produced running and jumping responses. Treatment with the 5-HT depletor p-chlorophenylalanine (300 mg/kg/day x 3, i.p.) lowered current thresholds to elicit orienting and running by 40 and 21%, respectively. Conversely, concurrent administration of the 5-HT uptake inhibitor fluoxetine (10 mg/kg, i.p.) and the 5-HT(1A) receptor antagonist WAY 100635 (0.5 mg/kg, s.c.) increased threshold currents to produce head and running movements by 41 and 18%, respectively. We investigated the anatomical substrate of this inhibitory effect of 5-HT with intracerebral 5-HT application by means of reverse microdialysis. Application of 5-HT (1-50 mM) into the midbrain immediately adjacent to the SC stimulation electrode resulted in a pronounced (approximately four-fold for 50 mM 5-HT) dose- and time-dependent increase in stimulation thresholds to elicit head movements. Application of 5-HT into the frontal cortex (up to 100 mM) had no significant effect on SC-evoked behavioral responses. These results show that 5-HT exerts an inhibitory influence over orienting and defensive behaviors initiated in the mammalian SC. It appears that this inhibitory effect is mediated, to a large extent, by a direct action of 5-HT at the level of the midbrain.  相似文献   

6.
The effect of intravenous (i.v.) serotonin (5-HT) on nociception and blood pressure in male Sprague-Dawley rats. Intravenous 5-HT produced a dose-dependent (6–192 μg/kg, i.v.) inhibition of the nociceptive tail-flick (TF) reflex in lightly pentobarbital-anesthetized (ED50 = 40 μg/kg) and conscious rats (ED50 = 44 μg/kg). In the lightly pentobarbital-anesthetized rat, the blood pressure response to i.v. 5-HT was typically a triphasic response with a marked Bezold-Jarisch reflex-induced decrease in pressure (associated with a brief period of apnea) followed by a pressor phase and a subsequent delayed hypotension. In the conscious rat, the response was typically biphasic with the late hypotensive phase absent. A variety of anatomical and pharmacological manipulations were to characterize the 5-HT-induced inhibition of the TF reflex and associated changes in blood pressure. Prevention of 5-HT-induced reflex apnea by artificial ventilation did not affect inhibition of the TF reflex produced by 5-HT. Pharmacological manipulations were performed to mimic, as closely as possible, the acute increases and decreases in blood pressure associated with i.v. 5-HT. Nitroprusside (8 μg/kg, i.v.) produced a decrease in blood pressure of similar magnitude and rate as that associated with the Bezold-Jarish reflec-induced decrease in pressure produced by 72 μg/kg 5-HT, but did not change TF latency from baseline. Similarly, acute increases in pressure produced by phenylphrine (8 μg/kg, i.v.), intended to mimic the secondary pressor effect of 5-HT, did not change TF latency. The short-acting ganglion blocker trimethaphan (5 mg/kg, i.v.) closely mimicked the late hypotensive phase produced by 5-HT but again resulted in no change in TF latency. Pretreatment with the ganglion blocker chlorisondamine (2.5 mg/kg) abolished all depressor responses to 72 μg/kg 5-HT, but did not significantly affect the TF reflex. These results indicate that acute changes in blood pressure and respiration associated with i.v. 5-HT do not contribute to inhibition of the TF reflex. This conclusion was confirmed in experiments in which bilateral vagotomy abolished approximately 70% of the 5-HT-induced inhibition of the TF reflex (and all depressor responses), and resulted in a significantly greater pressor response. Finally, low thoracic spinal cord transection (T9–10) abolished the inhibition of the TF reflex produced by i.v. 5-HT. Therefore, 5-HT stimulates vagal afferents and inhibits the TF reflex by activating descending inhibitory system from the brainstem. Taken together with the behavioral responses observed, these results support the notion that 5-HT, when administered i.v., is a noxious stimulus.  相似文献   

7.
K Kumaido 《Brain and nerve》1988,40(10):929-938
Respiratory control mechanism of the medullary raphe nuclei were studied with some references to their serotonergic mechanisms. Anesthetized, paralyzed and artificially ventilated cats were used and their phrenic nerve efferent activity was always observed as an indicator of central respiratory activity. Following results were obtained. 1) Electrical stimulation of medullary raphe nuclei, namely, nucleus raphe magnus, obscurus and pallidus, produced dominantly inhibitory responses in the phrenic nerve activity, while raphe stimulation in the pons and more rostral portion did not produce any respiratory responses. The blood pressure was depressed by raphe stimulation, too, almost in parallel to the respiratory inhibition. These inhibitory responses in respiration and blood pressure were partially antagonized by cyproheptadine (0.3-0.5 mg/kg i.v.) and methysergide (0.3-0.5 mg/kg i.v.). 2) Raphe stimulation inhibited remarkably activities of the medullary inspiratory and expiratory neurons, similarly. 3) In the experiment, where single shot stimulus was added to the raphe nuclei at the various time point in the respiratory phase, raphe stimulation showed the retardative effect of inspiratory switching, in addition to the inhibitory effect of phrenic burst activity. 4) The mechanism of respiratory inhibition produced by raphe stimulation was analyzed by evoked potentials in the averaged phrenic nerve activity. The post-stimulus averaged potentials of the phrenic nerve consist of the depolarizing potentials of about 10 msec duration and the subsequent hyperpolarizing potentials of several 10 msec duration, the duration time depending on the stimulus intensity. When stimulation was given in high frequency, the post-stimulus averaged potential became flattened, and the phrenic burst activity was inhibited almost completely. But in the case of stimulation in ventral parts of the raphe nuclei, the initial depolarizing potential was comparatively more prominent, and when high frequency stimulation was given, continuous firing was observed in the phrenic nerve activity. At the time of the continuous firing, respiratory rhythmicity was disappeared completely. 5) Propranolol (0.3-1.0 mg/kg i.v.), which have been recognized to have 5-HT1 antagonistic activity, reduced the hyperpolarizing potentials of the post-stimulus averaged potentials, and methysergide (0.3-1.0 mg/kg i.v.), 5-HT1 and 5-HT2 antagonist, reduced both depolarizing and hyperpolarizing potentials. These phenomena would suggest strongly that hyperpolarizing and depolarizing potentials are related to the 5-HT1 and 5-HT2 receptors, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)  相似文献   

8.
Unitary extracellular recordings were made from 51 convergent neurones in the dorsal horn of the lumbar spinal cords of urethane anaesthetized rats. All the cells tested responded to sustained noxious mechanical stimulation of their receptive fields on the ipsilateral hindpaw, but only 26/49 gave tonic responses lasting for more than 5 min. In all 26 cells, these tonic responses were depressed by diffuse noxious inhibitory controls (DNIC) triggered by applying noxious conditioning stimuli elsewhere on the body. In seven cells, the inhibitory effects could involve a complete abolition of activity and in five cells, when this occured, activity did not return during 2.5–6 min periods of observation following removal of the conditioning stimuli. However, in those cases, activity could be restored to pre-conditioning levels by further manipulations of the receptive field - either removal and re-application of the original stimulus or brief application of an additional stimulus. These results show that inhibitory controls can ‘switch-off’ activity in at least a small proportion of dorsal horn convergent neurones. One possible explanation would be that in these neurones, responses to sustained noxious stimuli may depend on activity in a positive feedback circuit within the central nervous system, which when interrupted, may be restored only by additional afferent inputs. The existence of such a loop could also explain the finding of convergent neurones which initially were not spontaneously active but which after stimulation of their receptive fields, developed on-going discharges which could be switched-off by DNIC.  相似文献   

9.
Diffuse noxious inhibitory controls (DNIC) are a mechanism of endogenous descending pain modulation and are deficient in a large proportion of chronic pain patients. However, the pathways involved remain only partially determined with several cortical and brainstem structures implicated. This study examined the role of the dorsal reticular nucleus (DRt) and infralimbic (ILC) region of the medial prefrontal cortex in DNIC. In vivo electrophysiology was performed to record from dorsal horn lamina V/VI wide dynamic range neurones with left hind paw receptive fields in anaesthetised sham‐operated and L5/L6 spinal nerve‐ligated (SNL) rats. Evoked neuronal responses were quantified in the presence and absence of a conditioning stimulus (left ear clamp). In sham rats, DNIC were reproducibly recruited by a heterotopically applied conditioning stimulus, an effect that was absent in neuropathic rats. Intra‐DRt naloxone had no effect on spinal neuronal responses to dynamic brush, punctate mechanical, evaporative cooling and heat stimuli in sham and SNL rats. In addition, intra‐DRt naloxone blocked DNIC in sham rats, but had no effect in SNL rats. Intra‐ILC lidocaine had no effect on spinal neuronal responses to dynamic brush, punctate mechanical, evaporative cooling and heat stimuli in sham and SNL rats. However, differential effects were observed in relation to the expression of DNIC; intra‐ILC lidocaine blocked activation of DNIC in sham rats but restored DNIC in SNL rats. These data suggest that the ILC is not directly involved in mediating DNIC but can modulate its activation and that DRt involvement in DNIC requires opioidergic signalling.  相似文献   

10.
In acute experiments in dogs anesthetized with pentobarbital, pressor responses produced by the i.v. injection of serotonin, noradrenaline and electric stimulation of the sympathetic nerves of the spleen, were registered before the i.v. injection of cianopramine (Ro 11-2465), a potent inhibitor of the uptake of serotonin into 5-HT neurones. Doses of 0.1 to 0.5 mg/kg of the antidepressant did not modify the blood pressure, while these produced a more intensive and prolonged pressor response during the i.v. injection of serotonin (p less than 0.05), noradrenaline (p less than 0.001) and stimulation of the splenic nerves (p less than 0.005). These effects resulted from the inhibition of the presynaptic reuptake of monoamines. The i.v. injection of 1-2 mg/kg of cianopramine produced significant hypotension (p less than 0.001) with baroreceptor and serotoninergic responses blockade. An induced strong hypertensive dose-dependent effect was observed after the i.v. administration of noradrenaline (+82%) and stimulation of splenic nerves (+80%). Cianopramine did not affect the hypotension produced by carbachol and histamine. The peripheric action of cianopramine showed a higher inhibitory effect on the presynaptic reuptake of noradrenaline than on serotonin.  相似文献   

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