Cardiovascular effects and changes in midbrain periaqueductal gray neuronal activity induced by electrical stimulation of the hypothalamus in the rat

The effects of low-intensity electrical stimulation of sites in the hypodalamus and zona incerta (ZI) on mean blood pressure (MBP), heart rate (HR), and neuronal activity in the midbrain periaqueductal gray (PAC) were investigated in rats. Long-lasting depressor responses were elicited from 67 sites in the hypothalamus and ZI. Effects on HR were variable, except for the ZI where bradycardic responses were evoked. The amplitude of the depressor responses was significantly correlated with baseline MBP on stimulation of the dorsomedial hypothalamic nucleus (DMH) or the dorsal hypothalamic area. Extracellular single-unit recordings were made from 94 PAG neurons. Most units were boated in the ventral half of the PAG (62/94), where spontaneous firing rates were significantly higher than in the dorsal half: 12.5 ± 1.4 spikes/s as compared to 6.0 ± 0.9 spikes/s. Changes in PAG neuronal activity to both ipsi- and contralaterel hypothalamic stimulation were observed. Most neurons were inhibited or unresponsive. There was no site specificity: responsive and unresponsive neurons were scattered throughout the PAG. Inhibition was most effectively evoked by stimulation of the DMH (25 out of 39 neurons) and the Zl (9 out of 15 neurons). In most neurons, the inhibition strictly followed the time course of hypothalamic stimulation. The results suggest that PAG as well as nonPAG pathways participate in the hypothalamic control of cardiovascular function.     

Distinct patterns of activated neurons throughout the rat midbrain periaqueductal gray induced by chemical stimulation within its subdivisions

This study provides a map of those neurons in the midbrain periaqueductal gray which are activated by chemical stimulation within different subdivisions of the periaqueductal gray. In pentobarbital anesthetized rats, the expression of the c-FOS protein was detected by immunocytochemistry and was used as a marker of neuronal activity. Microinjections of the γ-aminobutyric acid (GABA_A) receptor antagonist bicuculline (200 pmol in 50 nl) were used to increase selectively the firing rate of neurons originating from the injection site. The pattern of c-FOS immunoreactivity was highly specific for different injection sites. Dorsal injections were characterized by an extensive distribution of c-FOS immunoreactivity along the entire rostrocaudal extent of the periaqueductal gray, while ventral injections produced a much more restricted labeling. Following injection into the dorsal subdivision of the rostral periaqueductal gray, c-FOS immunoreactivity was present bilaterally in the dorsal and dorsolateral subdivisions of the rostral periaqueductal gray and was found in all subdivisions of the caudal periaqueductal gray. Dorsolateral injections at the level of the oculomotor nuclei produced strictly ipsilateral labeling in the dorsal and dorsolateral periaqueductal gray at the level of injection and throughout the ipsilateral half of the periaqueductal gray at more caudal levels. Stimulation in the ventrolateral periaqueductal gray induced FOS in the ventrolateral periaqueductal gray and the adjoining reticular formation. At rostral levels c-FOS immunoreactivity was also seen in the lateral periaqueductal gray but was absent caudal to the injection site. The identified patterns of activity in the periaqueductal gray provide a new basis for the interpretation of the diverse functional consequences of stimulation at periaqueductal gray sites. © 1995 Wiley-Liss, Inc.     

Actions of epinephrine on neurons in the rat midbrain periaqueductal gray maintained in vitro

The effect of epinephrine (EPI) on the activity of 150 periaqueductal gray (PAG) neurons was examined using extracellular recordings in an in vitro slice preparation. Drop application of EPI inhibited 45%, excited 35%, and had no effect on 20% of PAG neurons. Both the excitatory and inhibitory effects of EPI were of long duration; excitatory responses averaged 17 min and inhibitory responses averaged 11 min in duration. EPI responses could be blocked by specific alpha-1 and alpha-2 receptor antagonists. In 35% of the neurons tested, blockade of synaptic transmission by perfusion with low calcium-high magnesium physiological saline blocked responses to EPI. The effects of EPI were site specific: 77% of the cells in the caudal ventrolateral region of the PAG were inhibited by EPI; in all other regions of PAG equal numbers of cells were excited and inhibited by EPI. It is concluded that: (a) EPI has potent effects on a majority (80%) of PAG neurons; (b) EPI responses are mediated by presynaptic as well as postsynaptic mechanisms; (c) EPI preferentially inhibits neurons in the ventrolateral subdivision of caudal PAG. As this part of PAG contains many neurons that project to the ventral medulla, it is possible that EPI modulates the PAG-medullary functions such as analgesia, autonomic regulation, defense reactions, and sexual behaviors.     

Spinal afferents to functionally distinct periaqueductal gray columns in the rat: An anterograde and retrograde tracing study

The segmental and laminar organization of spinal projections to the functionally distinct ventrolateral (vlPAG) and lateral periaqueductal gray (lPAG) columns was examined by using retrograde and anterograde tracing techniques. It was found 1) that spinal input to both vlPAG and lPAG columns arose predominantly from neurons in the upper cervical (C1–4) and sacral spinal cord; 2) that there was a topographical separation of vl-PAG projecting and lPAG-projecting neurons within the upper cervical spinal cord; but 3) that below spinal segment C4, vlPAG-projecting and lPAG-projecting spinal neurons were similarly distributed, predominantly within contralateral lamina I, the nucleus of the dorsolateral fasciculus (the lateral spinal nucleus) and the lateral (reticular) part of lamina V. Consistent with the retrograde results, the greatest density of anterograde label, within both the vlPAG and lPAG, was found after tracer injections made either in the superficial or deep dorsal horn of the upper cervical spinal cord. Tracer injections made within the thoraco-lumbar spinal cord revealed that the vlPAG column received a convergent input from both the superficial and deep dorsal horn. However, thoraco-lumbar input to the lPAG was found to arise uniquely from the superficial dorsal horn; whereas the deep dorsal horn was found to innervate the “juxta-aqueductal” PAG region rather than projecting to the IPAG. These findings suggest that similar to spino-parabrachial projections, spinal projections to the lPAG (and juxta-aqueductal PAG) are topographically organised, with distinct subgroups of spinal neurons projecting to specific lPAG or juxta-aqueductal PAG subregions. In contrast, the vlPAG receives a convergent spinal input which arises from the superficial and deep dorsal horn of cervical, thoracic, lumbar, and sacral spinal segments. J. Comp. Neurol. 385:207–229, 1997. © 1997 Wiley-Liss, Inc.     

Electrophysiological analysis of midbrain periaqueductal gray influence on cardiovascular neurons in the ventrolateral medulla oblongata

Stimulation of sites in the rostral or caudoventral periaqueductal gray (PAG) results in substantial increases in mean blood pressure (MBP) and heart rate (HR). The efferent pathways from these PAG subregions possibly include a relay in the ventrolateral medulla oblongata (VLM), where neurons involved in maintaining vasomotor tone are located. Extracellular recordings were made from 21 cardiovascular neurons in the rostral VLM (RVLM) and from 6 cardiovascular neurons in the caudal VLM (CVLM) of the rat. These neurons showed barosensitivity and cardiac rhythmicity. In addition, the activity of 54 noncardiovascular and nonrespiratory units was recorded. Responses to electrical stimulation of sites in the (rostral or caudal) PAG were studied in 16 of the 21 cardiovascular RVLM neurons, the 6 CVLM neurons, and 46 of the 54 noncardiovascular neurons. Eight of the RVLM neurons were excited by rostral PAG stimulation; the poststimulus time histograms showed a constant latency in five units (32 ± 3 ms). This suggests the presence of relatively direct (although not monosynaptic) excitatory pathways from the rostral PAG to cardiovascular neurons in the RVLM, consisting of slowly conducting fibers (0.2-0.3 m/s). Five RVLM neurons did not respond to rostral PAG stimulation. Three units were tested with caudal PAG stimulation: one was excited, one inhibited, and one was unresponsive. The six cardiovascular CVLM neurons did not respond to PAG stimulation. Of the 46 noncardiovascular neurons, 14 cells were excited, 7 inhibited, and 2 cells antidromically activated. These results confirm earlier findings, extending them to the rostral PAG. They supply further evidence for the influence of the PAG on the cardiovascular function-related neuronal circuitry in the VLM.     

Orbitomedial prefrontal cortical projections to distinct longitudinal columns of the periaqueductal gray in the rat

We utilised retrograde and anterograde tracing procedures to study the origin and termination of prefrontal cortical (PFC) projections to the periaqueductal gray (PAG) in the rat. A previous study, in the primate, had demonstrated that distinct subgroups of PFC areas project to specific PAG columns. Retrograde tracing experiments revealed that projections to dorsolateral (dlPAG) and ventrolateral (vlPAG) periaqueductal gray columns arose from medial PFC, specifically prelimbic, infralimbic, and anterior cingulate cortices. Injections made in the vlPAG also labeled cells in medial, ventral, and dorsolateral orbital cortex and dorsal and posterior agranular insular cortex. Other orbital and insular regions, including lateral and ventrolateral orbital, ventral agranular insular, and dysgranular and granular insular cortex did not give rise to appreciable projections to the PAG. Anterograde tracing experiments revealed that the projections to different PAG columns arose from specific PFC areas. Projections from the caudodorsal medial PFC (caudal prelimbic and anterior cingulate cortices) terminated predominantly in dlPAG, whereas projections from the rostroventral medial PFC (rostral prelimbic cortex) innervated predominantly the vlPAG. As well, consistent with the retrograde data, projections arising from select orbital and agranular insular cortical areas terminated selectively in the vlPAG. The results indicate: (1) that rat orbital and medial PFC possesses an organisation broadly similar to that of the primate; and (2) that subdivisions within the rat orbital and medial PFC can be recognised on the basis of projections to distinct PAG columns.     

Cardiovascular effects of noradrenaline microinjected into the dorsal periaqueductal gray area of unanaesthetized rats

The periaqueductal grey area (PAG) is a mesencephalic region that is involved in the modulation of cardiovascular changes associated with behavioural responses. Among the neurotransmitters present in the PAG, noradrenaline (NA) is also known to be involved in central nervous system cardiovascular regulation. In the present study we report the cardiovascular effects of the microinjection of NA into the dorsal portion of the PAG (dPAG) of unanaesthetized rats and the peripheral mechanism involved in their mediation. Injection of NA in the dPAG of unanaesthetized rats evoked a dose-dependent pressor response accompanied by bradycardia. The magnitude of the pressor responses was higher at more rostral sites in the dPAG and decreased when NA was injected into the caudal portion of the dPAG. The responses to NA were markedly reduced in urethane-anaesthetized rats. The pressor response was potentiated by i.v. pretreatment with the ganglion blocker pentolinium and blocked by i.v. pretreatment with the vasopressin antagonist dTyr(CH2)5(Me)AVP. The results suggest that activation of noradrenergic receptors within the dPAG can evoke pressor responses, which are mediated by acute vasopressin release.     

Heterogeneous distribution of neurotensin-like immunoreactive neurons and fibers in the midbrain periaqueductal gray of the rat

The midbrain periaqueductal gray (PAG) has been shown to be a site where various manipulations induce pain suppression. Recent physiological evidence (Behbehani and Pert, 1984; Behbehani et al., 1987) suggests that neurotensin has pronounced physiological actions in PAG and effects pain suppression. We have performed immunohistochemical studies in order to determine the magnitude and distribution of neurotensin-like immunoreactive (NT-IR) cell bodies and fibers in PAG. NT-IR cell bodies were common throughout PAG, although there were more in the caudal than the rostral half. NT-IR neurons were much more numerous in the ventral than the dorsal half of PAG, and some appeared to be located within the dorsal raphe nucleus. The pattern of NT-IR fibers was analyzed with the aid of image enhancement/analysis and densitometry. The fibers were found to be heterogeneously distributed, being most heavily concentrated in the region adjacent to the cerebral aqueduct in the caudal two-thirds of PAG. The distribution of NT fibers closely matches sites where exogenously applied NT elicits long-lasting excitation of PAG neurons (Behbehani et al., 1987). Based on the known physiological and behavioral actions of NT in PAG, the present anatomical results suggest that NT acts on elements located predominantly in the medial and ventrolateral parts of PAG. Neurons activated by NT may project directly to the nucleus raphe magnus and adjacent ventral medulla (Behbehani and Pert, 1984) to activate neurons that project to the spinal cord and modulate nociceptive circuits.     

Chemical bladder irritation provokes c-fos expression in the midbrain periaqueductal gray matter of the rat

We investigated the topographical localization of c-fos expression in the midbrain periaqueductal gray matter (PAG) to detect nociception-induced neural activity in the PAG. In conscious female Wistar rats, c-fos expression was induced by continuous intravesical infusion of saline or 0.1% acetic acid. Number of c-fos protein (Fos)-positive cells was counted at each coronal section of the PAG as well as Barrington's nucleus. Fos-positive cells were also counted at L1 and L6 of the spinal cord, where most of the hypogastric and pelvic nerve afferent terminals project, respectively. Compared with saline infusion, acetic acid infusion provoked irritative bladder responses characterized by a marked increase in the frequency of bladder contractions, and induced a significant increase in the number of Fos-positive cells in both L1 and L6 of the spinal cord. Following acetic acid infusion, there was a significant increase in the number of Fos-positive cells in all coronal sections of the PAG compared with saline infusion, especially in the caudal part of the PAG. The increase in the number of Fos-positive cells was mainly observed in the ventrolateral and lateral parts of the caudal PAG, and in the dorsal part of the rostral PAG. However, there was no difference in the number of Fos-positive cells in Barrington's nucleus between saline and acetic acid infusion. In conclusion, nociception induced by chemical bladder irritation influences neural activity in the PAG. Implication of topographical difference in Fos expression in the PAG and its relevance to changes in bladder function remain to be elucidated.     

Stimulation of the midbrain periaqueductal gray modulates preinspiratory neurons in the ventrolateral medulla in the rat in vivo

The midbrain periaqueductal gray (PAG) is involved in many basic survival behaviors that affect respiration. We hypothesized that the PAG promotes these behaviors by changing the firing of preinspiratory (pre‐I) neurons in the pre‐Bötzinger complex, a cell group thought to be important in generating respiratory rhythm. We tested this hypothesis by recording single unit activity of pre‐Bötzinger pre‐I neurons during stimulation in different parts of the PAG. Stimulation in the dorsal PAG increased the firing of pre‐I neurons, resulting in tachypnea. Stimulation in the medial part of the lateral PAG converted the pre‐I neurons into inspiratory phase‐spanning cells, resulting in inspiratory apneusis. Stimulation in the lateral part of the lateral PAG generated an early onset of the pre‐I neuronal discharge, which continued throughout the inspiratory phase, while at the same time attenuating diaphragm contraction. Stimulation in the ventral part of the lateral PAG induced tachypnea but inhibited pre‐I cell firing, whereas stimulation in the ventrolateral PAG inhibited not only pre‐I cells but also the diaphragm, leading to apnea. These findings show that PAG stimulation changes the activity of the pre‐Bötzinger pre‐I neurons. These changes are in line with the different behaviors generated by the PAG, such as the dorsal PAG generating avoidance behavior, the lateral PAG generating fight and flight, and the ventrolateral PAG generating freezing and immobility. J. Comp. Neurol. 521: 3083–3098, 2013. © 2013 Wiley Periodicals, Inc.     

The medial preoptic nucleus of the hypothalamus modulates activity of nitric oxide sensitive neurons in the midbrain periaqueductal gray

Stimulation of the medial preoptic nucleus of the hypothalamus (MPO) has been shown to produce decreases in mean arterial pressure (MAP) by a pathway involving the periaqueductal gray region of the midbrain (PAG). Previous studies have shown that the injection of nitric oxide (NO) donating compounds into the dorsal PAG also decreases MAP, while the injection of nitric oxide synthase (NOS) inhibitors increases MAP. Collectively these studies suggest that the MPO elicited hypotensive response may involve NO production in PAG neurons. In this study, we investigated this hypothesis. We found that: (1) Bilateral injection of the NOS inhibitor 7-nitro indazole (7-NI) into the dorsolateral PAG cell columns produced elevations in MAP in a highly consistent and site specific fashion. (2) Microinjection of 7-NI in quantities that were too low to directly influence MAP blocked the MPO evoked hypotensive response in 9/11 cases. (3) While 41% of dorsal PAG neurons had baseline firing rates that were sensitive to 7-NI, 69% of PAG neuronal responses to MPO stimulation were blocked by 7-NI. (4) Inhibitory responses that were not blocked by 7-NI had significantly shorter latencies to onset in the presence of 7-NI. (5) PAG neurons that projected to the medulla exhibited similar electrophysiologic response patterns. Our results suggest the following: (1) The dorsolateral PAG contains a NO producing hypotensive network. (2) The MPO elicited hypotensive response may utilize this network. (3) Stimulation of the MPO elicits NO dependent responses from PAG neurons, some of which do project to medullary-cardiovascular control centers.     

刺激大鼠上矢状窦区硬脑膜对中脑导水管周围灰质核因子-κB蛋白表达的影响

目的 探讨核因子(NF)-κB蛋白在偏头痛痛觉信息的传递中的作用.方法 雄性SD大鼠,手术暴露其上矢状窦区(superior sagittal sinus,SSS)后电刺激该区硬脑膜,应用免疫组织化学染色技术观察中脑导水管(PAG)周围灰质NF-κB蛋白表达的变化.结果 空白组、假手术组、刺激组每张切片PAG区的NF-κB蛋白阳性神经元数分别为111.7±15.7、112.9±10.7、508.7±30.8,刺激组较其他组差异有统计学意义(t=-41.52,t=-36.21,均P＜0.05).结论 在PAG区出现NF-κB细胞的激活,表明NF-κB蛋白在偏头痛的发生及发展过程中起到了一定作用.     

Behavioral and c-fos expression changes induced by nitric oxide donors microinjected into the dorsal periaqueductal gray

The dorsolateral periaqueductal gray matter (DLPAG) is a key structure in behavioral and autonomic expression of defensive reactions. Inhibitors of nitric oxide (NO) synthase microinjected into the DLPAG are anxiolytic. The purpose of the present study was to evaluate the behavioral effects produced by administration of two NO donors, SIN-1 or DEA/NO, into the DLPAG. We also employed the detection of Fos-like immunoreactivity (FLI) to reveal brain areas activated by SIN-1 administration. Male Wistar rats (n = 7-11/group) received intra-DLPAG injection of SIN-1 (150 or 300 nmol), DEA/NO (150, 300, or 600 nmol), or saline (0.5 microl), and their behavior was observed in an open arena during 15 min. For the FLI assay, the animals (n = 3-5/group) were sacrificed 2.25 h after the drug. In a second experiment, rats (n = 5-7/group) received a first intra-DLPAG injection of saline or methylene blue (MB, 30 nmol), an NO antagonist, followed by saline or SIN-1 (300 nmol). SIN-1 (300 nmol) induced a flight response characterized by coordinated running and oriented jumps with escape attempts. Similar but short-lasting changes were seen after the administration of DEA/NO. FLI was dose-dependently induced by SIN-1 in several regions related to defensive reactions, including the periaqueductal gray, hypothalamic nuclei, medial amygdala, and cingulate cortex (analysis of variance, p < 0.05). A greater number of neurons showing FLI was found ipsilateral to the microinjection site. The drug effect was greater at this side in the bed nucleus of the stria terminalis, paraventricular and lateral hypothalamus, cingulate cortex, septohipoccampal nucleus, and horizontal limb of the diagonal band. The increase in SIN-1-induced FLI was attenuated by MB pretreatment in most regions. These results suggest that NO may participate in the modulation of defensive responses in the DLPAG.     

Columnar distribution of catecholaminergic neurons in the ventrolateral periaqueductal gray and their relationship to efferent pathways

The periaqueductal gray (PAG) is a critical brain region involved in opioid analgesia and provides efferents to descending pathways that modulate nociception. In addition, the PAG contains ascending pathways to regions involved in the regulation of reward, including the substantia nigra (SN) and the ventral tegmental area (VTA). SN and VTA contain dopaminergic neurons that are critical for the maintenance of positive reinforcement. Interestingly, the PAG is also reported to contain a population of dopaminergic neurons. In this study, the distribution of catecholaminergic neurons within the ventrolateral (vl) PAG was examined using immunocytochemical methods. In addition, the catecholaminergic PAG neurons were examined to determine whether these neurons are integrated into ascending (VTA, SN) and descending rostral ventral medulla (RVM) efferent pathways from this region. The immunocytochemical analysis determined that catecholaminergic neurons in the PAG are both dopaminergic and noradrenergic and these neurons have a distinct rostrocaudal distribution within the ventrolateral column of PAG. Dopaminergic neurons were concentrated rostrally and were significantly smaller than noradrenergic neurons. Combined immunocytochemistry and tract tracing methods revealed that catecholaminergic neurons are distinct from, but closely associated with, both ascending and descending efferent projection neurons. Finally, by electron microscopy, catecholaminergic neurons showed close dendritic appositions with other neurons in PAG, suggesting a possible nonsynaptic mechanism for regulation of PAG output by these neurons. In conclusion, our data indicate that there are two populations of catecholaminergic neurons in the vlPAG that form dendritic associations with both ascending and descending efferents suggesting a possible nonsynaptic modulation of vlPAG neurons. Synapse, 2013. © 2012 Wiley Periodicals, Inc.     

Opiate withdrawal increases ProTRH gene expression in the ventrolateral column of the midbrain periaqueductal gray

The midbrain periaqueductal gray matter (PAG) has a critical role in the modulation of behavioral and autonomic manifestations of the opiate withdrawal syndrome. We report a nearly 5-fold increase in proTRH gene expression in neurons of the ventrolateral column of the PAG following naltrexone precipitated morphine withdrawal. The accumulation of immunoreactive proTRH-derived peptides, but not the mature TRH tripeptide was concomitantly observed in these cells. These findings indicate that proTRH-derived peptides synthesized in neurons of the ventrolateral PAG may function as modifiers of opiate withdrawal responses.     

Intracranial haemorrhage induced at arterial pressure in the rat: Part 2: Short term changes in local cerebral blood flow measured by autoradiography

The regional distribution of blood flow following intracranial haemorrhage at arterial pressure was measured with the ¹⁴C-iodoantipyrine autoradiographic technique in Sprague Dawley Rats. With uncontained haemorrhage, there was a bilateral reduction in cerebral blood flow, associated with a fall in cerebral perfusion pressure. With contained intracerebral haemorrhage there was a profound ipsilateral reduction in flow in the hemisphere adjacent to the haematoma. This study, indicates that extensive cerebral ischaemia occurs immediately after an intracerebral haemorrhage, and that this may be the result of compression of the microcirculation.     

Antidepressant treatment reduces Fos-like immunoreactivity induced by swim stress in different columns of the periaqueductal gray matter

Antidepressant treatment attenuates behavioral changes induced by uncontrollable stress. The periaqueductal gray matter (PAG) is proposed to be a brain site involved in the behavioral responses to uncontrollable stress and antidepressant effects. The main goal of the present study was to investigate the effect of antidepressant treatment on the pattern of neural activation of the PAG along its mediolateral and rostrocaudal subregions after a forced swim stress episode. Male Wistar rats were sub-acutely treated with desipramine (a selective noradrenaline re-uptake blocker, three injections of 10 mg/kg in 24 h) or clomipramine (a non-selective serotonin and noradrenaline re-uptake blocker, three injections of 10 mg/kg in 24 h) and submitted to the forced swimming test (FST). Two hours after the test their brain were removed for Fos immunohistochemistry. Fos-like immunoreactivity (FLI) in rostral, intermediate and caudal portions of dorsomedial (dmPAG), dorsolateral (dlPAG), lateral (lPAG) and ventrolateral (vlPAG) PAG were quantified by a computerized system. The FST session increased FLI in most parts of the PAG. Previous treatment with desipramine or clomipramine reduced FLI in all columns of the PAG. FLI in the PAG correlated positively with to the immobility time and negatively with to climbing behavior scored during the test. These results indicate that neurons in the PAG are activated by uncontrollable stress. Moreover, inhibitory action of antidepressants on this activity may be associated with the anti-immobility effects of these drugs in the FST.     

Relationship between analgesia and cardiovascular changes induced by electrical stimulation of the mesencephalic periaqueductal gray matter in the rat

Analgesia and cardiovascular changes produced by electrical stimulation of the midbrain periaqueductal gray matter were examined in the lightly pentobarbital-anesthetized rat. The current intensity required to elicit analgesia was first determined, using the tail-flick test, after which the effects on arterial pressure and heart rate were recorded from stimulating at the same intensity. Intensity thresholds for decreases and/or increases in arterial pressure were also ascertained at the same sites. Although stimulation at the analgesia threshold produced increases in arterial pressure at more than 60% of the sites within the periaqueductal gray, decreases, no change, and mixed responses were also observed. Below the periaqueductal gray, increases in arterial pressure occurred at analgesia threshold for more than 70% of the sites studied, and no cardiovascular changes were found for 20% of the sites. Above the periaqueductal gray, no change and mixed responses were the predominant effects at analgesia threshold. A correlation across sites within the periaqueductal gray was found between the threshold for stimulation-produced analgesia and the threshold for a change in arterial pressure. No reliable alterations in heart rate were observed at any stimulation site. These results are in agreement with the existence of a common midbrain substrate for both the regulation of pain inhibition and cardiovascular function. However, they indicate that analgesia resulting from stimulation of the periaqueductal gray matter does not necessarily occur concurrently with an increase in arterial pressure.     

Inhibition of the responses of neurons in the rat spinal cord to noxious skin heating by stimulation in midbrain periaqueductal gray or lateral reticular formation

Single units responsive to noxious heating of glabrous hindfoot skin were recorded in the lumbar spinal cord of rats anesthetized with sodium pentobarbital. Unit responses to heat stimuli (e.g. 50 degrees C, 10 s) delivered at 2-min intervals were stable and were markedly suppressed during stimulation (100-ms pulse trains at 100 Hz, 3/s, 25-400 microA) in the midbrain periaqueductal gray (PAG) or lateral reticular formation (LRF). Inhibition did not appear to outlast the midbrain stimulation period. By systematically varying the position of an array of 3 or 5 stimulating electrodes, we observed that stimulation in PAG and subjacent tegmental areas, as well as in widespread regions of the LRF bilaterally, suppressed unit responses to noxious skin heating. The degree of suppression of unit responses increased with graded increases in PAG or LRF stimulation intensity. LRF appeared to be more efficacious than PAG stimulation, based on lower currents at threshold, as well as on significantly greater slopes in current-inhibition plots for LRF compared to PAG stimulation. Unit responses increased linearly with graded increases in stimulus temperature from 42 to 54 degrees C. Slopes of temperature-response lines were reduced during PAG stimulation with no change in response threshold, while temperature-response lines were shifted in a parallel manner toward higher temperatures during LRF stimulation with an increase in response threshold. The results suggest that differential inhibitory systems are activated by PAG or LRF stimulation and are discussed in relation to previous findings in the cat and as a possible mechanism of stimulation-produced analgesia.     

Partial involvement of monoamines and opiates in the inhibition of rat spinal nociceptive neurons evoked by stimulation in midbrain periaqueductal gray or lateral reticular formation

In rats anesthetized with sodium pentobarbital, we tested the effects of systemic or intrathecal administration of the opiate antagonist naloxone, the serotonergic antagonist methysergide, or the adrenergic antagonist phentolamine, on inhibition produced by electrical stimulation in midbrain periaqueductal gray (PAG) or lateral reticular formation (LRF) of the responses of single lumbar dorsal horn neurons to noxious heating (50-54 degrees C, 10 s) of hindpaw skin. Systemically administered naloxone (1-10 mg/kg i.v.) reduced (greater than 20% below predrug inhibition) inhibition from PAG and/or LRF in 5/12 units and had no effect in the remainder. Systemic methysergide (2-6 mg/kg i.v.) selectively reduced PAG-evoked inhibition in 6 units, while inhibitions from both PAG and LRF stimulation were reduced in one unit and unaffected in 8 units. Systemic phentolamine (2-4 mg/kg) reduced LRF-evoked inhibition in 4 units, while inhibitions from PAG and LRF were reduced in one unit and unaffected in 5. Intrathecally applied methysergide reduced or abolished PAG-evoked inhibition in 8/16 units and reduced or abolished LRF-evoked inhibition in 6/14 units. Reductions in the level of inhibition were reversible in one-half of the cases, whereas they persisted for over 2 h in the remainder. The mixed effects of both systemically and intrathecally administered drugs suggest that monoamines and opiates may be partly involved in spinal inhibitory mechanisms activated from the midbrain.