Activity of neurons of the cerebral A5 zone of rat induced by adequate stimulation of muscle afferents: On the control of arterial pressure and respiration during muscle activity

In experiments on 24 anesthetized rats with preserved spontaneous respiration, we first recorded the volley impulse activity of neurons (n = 30) in the brainstem A5 zone, which was induced by periodical stretchings of the forelimb flexors and hindlimb extensors. The frequency of action potentials in such volleys was, on average, 99.7 ± 19.6 sec⁻¹. In the course of this kinesthetic stimulation, along with the activation of “proprioceptive” neurons of the A5 zone, we observed transitory drops in the arterial pressure and increases first recorded the activity of baroceptive neurons in subpial parts of the A5 zone (n = 4); the frequency of their background impulsation was, on average, 25.1 ± 0.8 sec⁻¹. This activity in all cases was transitorily suppressed both upon increases of the blood pressure caused by constriction of the carotid arteries or nociceptive tail stimulation, as well as upon stretching of skeletal muscles. Therefore, we first obtained direct proof that neuronal systems of the A5 zone are involved in integration of visceral and somatic proprioceptive afferent influences. We hypothesize that the physiological role of this mechanism of integration of somatic and visceral information at the level of the A5 zone is directed toward lowering of the arterial pressure and intensification of respiration within the period of intensified motor activity. This mechanism is based on the interaction between “proprioceptive,” baroceptive, and, perhaps, multiceptive neurons within the A5 zone. Neirofiziologiya/Neurophysiology, Vol. 39, No. 6, pp. 443–452, November–December, 2007.     

Postsynaptic Reactions in Somatosensory Cortex Neurons Activated by Stimulation of Nociceptors: Modulation upon Stimulation of the Central Grey, <Emphasis Type="Italic">Locus Coeruleus</Emphasis>, and <Emphasis Type="Italic">Substantia Nigra</Emphasis>

In experiments on cats, we studied the effects of electrical stimulation of the cerebral central grey (CG), locus coeruleus (LC), and substantia nigra (SN) on postsynaptic processes evoked by nociceptive volleys in somatosensory cortex neurons. Nineteen cells activated exclusively by stimulation of nociceptors (intense stimulation of the dental pulp) and 26 cells activated by both nociceptive and non-nociceptive (near-threshold) stimulations of the n. infraorbitalis and thalamic nucl. ventroposteromedialis (VPM) were intracellularly recorded (nociceptive and convergent cortical neurons, respectively). In neurons of both groups, stimulation of both nociceptive afferents and the VPM evoked complex responses having on EPSP-spike-IPSP patterns (duration of IPSPs about 200-300 msec). Electrical stimulation of the СG, which per se could activate the examined cortical neurons, induced prolonged suppression of synaptic responses evoked by stimulation of nociceptors; maximum inhibition was observed at 600- to 800-msec-long conditioning–test intervals. A certain parallelism was observed between the conditioning effects of СG stimulation and effects of systemic introduction of morphine. Isolated stimulations of the LC and SN by short high-frequency pulse series evoked primary complex EPSPs in a part of the examined cortical neurons, while high-amplitude IPSPs (up to 120 msec long) were observed in other units. Independently of the type of the primary response, conditioning stimulations of the LC and SN induced long-lasting (several seconds) suppression of synaptic responses evoked in cortical neurons by stimulation of nociceptive inputs. Mechanisms of modulating influences coming from opioidergic, noradrenergic, and dopaminergic cerebral systems to neurons of the somatosensory cortex activated upon excitation of high-threshold (nociceptive) afferent inputs are discussed.     

Raphe Stimulation-Evoked Modulation of Postsynaptic Responses by Neurons of the Cat Somatosensory Cortex Activated by Stimulation of Nociceptors

We studied the effects of electrical stimulation of the raphe nuclei (RN) of the cat brain on postsynaptic potentials developing in somatosensory cortex neurons activated by nociceptive influences. Intracellular records were obtained from 15 cells, which were either selectively excited by stimulation of nociceptors (intense electrical stimulation of the dental pulp) or activated by both the above nociceptive and non-nociceptive (moderate stimulations of the infraorbital nerve or thalamic ventroposteromedial nucleus, VPMN) influences. In neurons of both groups, stimulation of both nociceptive afferents and the VPMN evoked complex responses (EPSP–AP–IPSP; IPSPs were 200 to 300 msec long). In some studied cortical neurons, isolated electrical stimulation of the RN (which caused the release of serotonin, 5-HT, in the cortex) resulted in relatively short-latency synaptic excitation, while inhibition was observed in other cells. In the case where stimulation of the RN was used as conditioning influence, such stimulation (independently of the kind of the initial response to RN stimulation) led to long-latency and long-lasting suppression of all components of the synaptic reactions evoked by excitation of nociceptors. The maximum of inhibition was observed at test intervals of 300 to 800 msec. The mechanisms underlying modulatory influences coming from the 5-HT-ergic brainstem system to neurons of the somatosensory cortex, which are activated by excitation of high-threshold (nociceptive) afferent inputs, are discussed.     

Effects of Stimulation of the Periaqueductal Gray and <Emphasis Type="Italic">Locus Coeruleus</Emphasis> on Postsynaptic Reactions of Cat Somatosensory Cortex Neurons Activated by Nociceptors

In cats, we studied the influences of stimulation of the periaqueductal gray (PAG) and locus coeruleus (LC) on postsynaptic processes evoked in neurons of the somatosensory cortex by stimulation of nociceptive (intensive stimulation of the tooth pulp) and non-nociceptive (moderate stimulations of the infraorbital nerve and ventroposteromedial nucleus of the thalamus) afferent inputs. Twelve cells activated exclusively by nociceptors and 16 cells activated by both nociceptive and non-nociceptive influences (hereafter, nociceptive and convergent neurons, respectively) were recorded intracellularly. In neurons of both groups, responses to nociceptive stimulation (of sufficient intensity) looked like an EPSP-spike-IPSP (the latter, of significant duration, up to 200 msec) complex. Electrical stimulation of the PAG (which could itself evoke activation of the cortical neurons under study) resulted in long-term suppression of synaptic responses evoked by excitation of nociceptors (inhibition reached its maximum at a test interval of 600 to 800 msec). We observed a certain parallelism between conditioning influences of PAG activation and effects of systemic injections of morphine. Isolated stimulation of LC by a short high-frequency train of stimuli evoked primary excitatory responses (complex EPSPs) in a part of the examined cortical neurons, while in other cells high-amplitude and long-lasting IPSP (up to 120 msec) were observed. Independently of the type of the primary response to PAG stimulation, the latter resulted in long-term (several seconds) suppression of the responses evoked in cortical cells by stimulation of the nociceptive inputs. The mechanisms of modulatory influences coming from opioidergic and noradrenergic brain systems to somatosensory cortex neurons activated due to excitation of high-threshold (nociceptive) afferent inputs are discussed.Neirofiziologiya/Neurophysiology, Vol. 37, No. 1, pp. 61–73, January–February, 2005.     

Monoamines and neuropeptides interact to inhibit aversive behaviour in Caenorhabditis elegans

Pain modulation is complex, but noradrenergic signalling promotes anti-nociception, with α(2)-adrenergic agonists used clinically. To better understand the noradrenergic/peptidergic modulation of nociception, we examined the octopaminergic inhibition of aversive behaviour initiated by the Caenorhabditis elegans nociceptive ASH sensory neurons. Octopamine (OA), the invertebrate counterpart of norepinephrine, modulates sensory-mediated reversal through three α-adrenergic-like OA receptors. OCTR-1 and SER-3 antagonistically modulate ASH signalling directly, with OCTR-1 signalling mediated by Gα(o). In contrast, SER-6 inhibits aversive responses by stimulating the release of an array of 'inhibitory' neuropeptides that activate receptors on sensory neurons mediating attraction or repulsion, suggesting that peptidergic signalling may integrate multiple sensory inputs to modulate locomotory transitions. These studies highlight the complexity of octopaminergic/peptidergic interactions, the role of OA in activating global peptidergic signalling cascades and the similarities of this modulatory network to the noradrenergic inhibition of nociception in mammals, where norepinephrine suppresses chronic pain through inhibitory α(2)-adrenoreceptors on afferent nociceptors and stimulatory α(1)-receptors on inhibitory peptidergic interneurons.     

Neurophysiological analysis of efferent-afferent interaction of neurons of the parietal associate cortex in cats

Neuronal responses of the parietal associate cortex (field 5) was recorded in waking cat during electrical stimulation of the pyramidal tract axons and afferent stimulation. The electrical stimulation of the pyramid evoked marked responses in 39% of neurons. 87% of these neurons increased spike activity during sematic nociceptive stimulation, 61% of test neurons were activated by light or tonal stimulation. Neuronal activity was recorded during defensive conditioning to the pyramidal tract axons stimulation. It has been shown that conditioned stimulation of the pyramidal tract evoked plastic changes of responses in 66% of neurons of the parietal cortex. These data are discussed relative to the possible functional role of the efferent-afferent interaction to field 5.     

Effects of 5-HT3 receptor blockade on visceral nociceptive neurons in the ventrolateral reticular field of the rat medulla oblongata

The caudal ventrolateral reticular formation of the medulla oblongata is the first layer of visceral nociceptive processing. In experiments on rats, neuronal responses in this zone to nociceptive stimulation of the large intestine were examined and the effects of selective blockade of 5-HT3 receptors on these responses were assessed. By the character of responses to nociceptive colorectal stimulation (CRS), the recorded medullary neurons were divided into three groups—excited, inhibited and indifferent. Intravenous injection of 5-HT3 antagonist granisetron (1 and 2 mg/kg) as well as local application of this agent on the surface of the medulla oblongata (1.25 and 2.5 nmole) suppressed the background and evoked firing of CRS-excited reticular neurons in a dose-dependent manner but did not exert as pronounced influence on the cells inhibited by visceral nociceptive stimulation. Spike activity in the group of CRS-indifferent neurons under similar conditions was 5-HT3-independent. The results obtained provide evidence that 5-HT3 receptors mediate the facilitating effect of serotonin on supraspinal transmission of the abdominal nociceptive stimulus which, at least in part, is realized via selective activation of visceral medullary nociceptive neurons. A shutdown of this mechanism may underlie the analgesic effect of 5-HT3 antagonists in abdominal pain syndromes.     

会阴部皮肤和盆腔内脏的伤害感受性信息在猫骶髓后连合核神经元的汇聚

在戊巴比妥钠麻醉的猫上,用玻璃微电极细胞外记录的方法,观察了躯体和内脏的伤害性刺激对骶髓后连合核神经元活动的影响。结果表明,所有接受盆神经内Ａδ纤维传入的神经元皆为特异性伤害感受或广动力范围神经元－它们可被包括会阴部皮肤的躯体感受野的机械性及强电刺激诱发。上述结果提示,Ａδ纤维可能在盆腔内脏的伤害感受性传递中起重要作用。     

红核在肌梭传入抑制伤害性反应中的作用

本实验用玻璃微电极细胞外记录方法, 观察了刺激红核对皮肤强电刺激诱发的大鼠脊髓背角广动力范围（ｗｉｄｅ ｄｙｎａｍｉｃ ｒａｎｇｅ, ＷＤＲ） 神经元长潜伏期反应（Ｃ反应） 的作用, 及红核对琥珀胆碱（ｓｕｃｃｉｎｙｌｃｈｏｌｉｎｅ,ＳＣＨ） 诱发的肌梭传入抑制ＷＤＲ神经元Ｃ反应效应的影响。结果表明： 电刺激红核对ＷＤＲ 神经元Ｃ反应具有抑制作用, 此作用可被静注噻庚啶明显减弱。静脉注射ＳＣＨ 对ＷＤＲ神经元Ｃ反应有明显抑制作用, 损毁单侧红核后,ＳＣＨ 对ＷＤＲ神经元Ｃ反应的抑制效应明显减弱。结果提示,５ＨＴ参与红核的痛下行抑制作用, 在肌梭传入镇痛中红核起着一定的作用     

Plasticity and emerging role of BKCa channels in nociceptive control in neuropathic pain

Large‐conductance Ca²⁺‐activated K⁺ (BK_Ca, MaxiK) channels are important for the regulation of neuronal excitability. Peripheral nerve injury causes plasticity of primary afferent neurons and spinal dorsal horn neurons, leading to central sensitization and neuropathic pain. However, little is known about changes in the BK_Ca channels in the dorsal root ganglion (DRG) and spinal dorsal horn and their role in the control of nociception in neuropathic pain. Here we show that L5 and L6 spinal nerve ligation in rats resulted in a substantial reduction in both the mRNA and protein levels of BK_Ca channels in the DRG but not in the spinal cord. Nerve injury primarily reduced the BK_Ca channel immunoreactivity in small‐ and medium‐sized DRG neurons. Furthermore, although the BK_Ca channel immunoreactivity was decreased in the lateral dorsal horn, there was an increase in the BK_Ca channel immunoreactivity present on dorsal horn neurons near the dorsal root entry zone. Blocking the BK_Ca channel with iberiotoxin at the spinal level significantly reduced the mechanical nociceptive withdrawal threshold in control and nerve‐injured rats. Intrathecal injection of the BK_Ca channel opener [1,3‐dihydro‐1‐[2‐hydroxy‐5‐(trifluoromethyl)phenyl]‐5‐(trifluoromethyl)‐2H‐benzimidazol‐2‐one] dose dependently reversed allodynia and hyperalgesia in nerve‐ligated rats but it had no significant effect on nociception in control rats. Our study provides novel information that nerve injury suppresses BK_Ca channel expression in the DRG and induces a redistribution of BK_Ca channels in the spinal dorsal horn. BK_Ca channels are increasingly involved in the control of sensory input in neuropathic pain and may represent a new target for neuropathic pain treatment.     

Effect of vasopressin on neuronal responses of theNucl. Caudalis of the spinal trigeminal tract in rats

Effect of vasopressin on responses of individual neurons of thenucl. caudalis of the spinal trigeminal tract was studied on rats under urethan anesthesia; the responses were evoked by nociceptive (stimulation of the tooth pulp) or non-nociceptive (stimulation of Aa fibers of the infraorbital nerve) afferent activation. After injection of 10 nM vasopressin into the recording zone, responses evoked by stimulation of the tooth pulp were suppressed in all studied neurons of the high-threshold group; the same was true as to responses induced by stimulation of the tooth pulp and infraorbital nerve in most neurons of the convergent group. At the same time, vasopressin did not change the responses evoked by stimulation of Aa fibers of the infraorbital nerve in neurons of the low-threshold group. Possible involvement of vasopressin in the process of pain suppression is discussed.     

The effect of electroacupuncture on the neuronal responses of the oral trigeminal nucleus in the cat during nociceptive and non-nociceptive stimulation

Effects of electroacupuncture (EAP) on the responses of different functional types of neurons of the oral trigeminal nucleus (OTN) by nociceptive and non-nociceptive stimulation were studied in acute experiments on adult cats. It was demonstrated that the main part of neurons of the OTN is a wide dynamic range of neurons. Characteristic feature of the OTN is neurons with low-threshold pulp afferent input. EAP inhibit nociceptive responses of neurons (preferentially nonspecific neurons), while responses to non-nociceptive stimulation are not changed at all. The results are discussed from the point of view that OTN takes part in nociceptive and non-nociceptive reactions.     

Somatosensory afferent inputs release 5-HT and NA from the spinal cord

Endogenous serotonin (5-HT) and noradrenaline (NA) release by somatosensory afferent inputs was investigated at the level of the spinal cord using in vivo microdialysis technique combined with high performance liquid chromatography and electrochemical detection (HPLC-ECD). Selective stimulation of large myelinated Aβ afferent fibers significantly increased 5-HT release to 151.1 ±10.1% of the control, but did not affect NA release. However, selective stimulation of small myelinated Aδ fibers released NA rather than 5-HT. The NA level enhanced to 128.8±6.4% of the control after Aδ fibers were stimulated with the intensity of 6 times threshold. Stimulation of unmyelinated C fibers unavoidably excited the Aβ and Aδ afferent fibers, causing both 5-HT and NA release from the spinal cord. The results suggest that both innocuous and noxious information may activate serotonergic descending pathways. The noradrenergic descending pathways are only triggered by noxious inputs transmitted by small afferent fibers.     

c-Fos expression in rat brain stem and spinal cord in response to activation of cardiac ischemia-sensitive afferent neurons and electrostimulatory modulation

The purpose of this study was to identify central neuronal sites activated by stimulation of cardiac ischemia-sensitive afferent neurons and determine whether electrical stimulation of left vagal afferent fibers modified the pattern of neuronal activation. Fos-like immunoreactivity (Fos-LI) was used as an index of neuronal activation in selected levels of cervical and thoracic spinal cord and brain stem. Adult Sprague-Dawley rats were anesthetized with urethane and underwent intrapericardial infusion of an "inflammatory exudate solution" (IES) containing algogenic substances that are released during ischemia (10 mM adenosine, bradykinin, prostaglandin E2, and 5-hydroxytryptamine) or occlusion of the left anterior descending coronary artery (CoAO) to activate cardiac ischemia-sensitive (nociceptive) afferent fibers. IES and CoAO increased Fos-LI above resting levels in dorsal horns in laminae I-V at C2 and T4 and in the caudal nucleus tractus solitarius. Dorsal rhizotomy virtually eliminated Fos-LI in the spinal cord as well as the brain stem. Neuromodulation of the ischemic signal by electrical stimulation of the central end of the left thoracic vagus excited neurons at the cervical and brain stem level but inhibited neurons at the thoracic spinal cord during IES or CoAO. These results suggest that stimulation of the left thoracic vagus excites descending inhibitory pathways. Inhibition at the thoracic spinal level that suppresses the ischemic (nociceptive) input signal may occur by a short-loop descending pathway via signals from cervical propriospinal circuits and/or a longer-loop descending pathway via signals from the nucleus tractus solitarius.     

Effects of basolateral amygdalar nuclei on neuronal activity in the medullary respiratory center under hypoxia conditions

The effect of stimulation of the basolateral nuclei of the amygdala (ABL) on the impulse activity of respiratory neurons (RNs) of the rat medulla and the respiratory function was studied in the norm and under conditions of oxygen deficiency. Electrical stimulation of the ABL under conditions of normal atmospheric pressure exerted ambivalent effects on bulbar RNs; both activation and inhibition of these neurons were observed, but inhibitory effects noticeably prevailed. Electrical stimulation of the ABL within an initial phase of hypobaric hypoxia corresponding to ascent to a 4,000 to 5,000 m altitude exerted mostly inhibitory effects on the RN activity (similarly to what was observed under normoxia conditions). Stimulation of these nuclei within a phase of intensive hypoxia (7,500 to 8,000 m) evoked no typical responses of such neurons against the background of hypoxic suppression of their activities. Neirofiziologiya/Neurophysiology, Vol. 38, No. 4, pp. 292–297, July–August, 2006.     

Interaction of the monoaminergic and opioidergic brain systems in the course of nociceptive and antinociceptive reactions in cats

Nociceptive responses were evoked in cats by electrical transcutaneous stimulation of the forepaw or electrical stimulation of respective brain structures; these responses could be modulated (intensified or suppressed) by combined electrical stimulation of different brain structures or by neurochemical influences upon these structures. Intensification of nociceptive responses was observed after stimulation of the noradrenergic orP-ergic systems localized in the ventral zone of the central gray (vl SGC) and the structures monosynaptically connected with the latter: the posterior and lateral hypothalamic nuclei (Hp andHl) and preoptic region (RPO). Similar effects were induced by suppression of the serotoninergic system concentrated within the dorsolateral central gray (dl SGC), dorsal raphe nucleus (Rd), and closely related structures: the ventromedial, dorsomedial, and paraventricular hypothalamic nuclei (Hvm, Hdm, andHpv), septum (Sep), basolateral amygdalar nucleus (Am bl), fields 3–4 of the hippocampus (CA3–4), and cingular cortex (GC). Suppression of the serotoninergic system resulted in a decrease in the levels of functioning of the met-enkephalin- and β-endorphinergic systems and facilitation of theP-ergic system. Moderation of nociceptive responses, i.e., an analgesic effect, was observed after either stimulation of the serotonin-, met-enkephalin-, and β-endorphinergic systems localized in thedl SGC, Rd, Hvm, Hdm, Sep, Am bl, CA3–4, andGC, or suppression of the noradrenergic system. The latter influence resulted in inhibition of theP-ergic system and a rise in the functional activity of the met-enkephalin- and β-endorphinergic systems. The composition of two antagonistic brain systems, nociceptive and antinociceptive, is considered. The antinociceptive system includes serotonin-, met-enkephalin-, and β-endorphinergic elements. Leu-enkephalin is a nonspecific activator of the met-enkephalin-, β-endorphin-, andP-ergic systems. The nociceptive system consists of thevl SGC, Hp, Hl, andRPO, while the antinociceptive system includes thedl SGC, Rd, Hvm, Hdm, Hpv, Sep, Am dl, CA3–4, andGC.     

Impulse activity of the bulbar cardiovascular neurons during myocardial ischemia and stimulation of the cortical sensorimotor zone

In acute experiments on cats performed under nembutal anesthesia the stimulation of sensorimotor zone in cerebral hemisphere cortex changed the impulse activity of interneurons of bulbar cardiovascular centre and not of the afferent neurons. The analysis of the activity of afferent neurons and interneurons has shown a decrease in coordination between the reaction of these cells to the development of ischemic myocardial lesions during the cortex stimulation. In these conditions bulbar cardiovascular neurons could both increase and decrease the impulse activity. These changes seem to be the reason for the growing incidence of idioventricular ischemic arrhythmias during cortical stimulation.     

Visceral nociception: peripheral and central aspects of visceral nociceptive systems

Discomfort and pain are the sensations most commonly evoked from viscera. Most nociceptive signals that originate from visceral organs reach the central nervous system (c.n.s.) via afferent fibres in sympathetic nerves, whereas parasympathetic nerves contain mainly those visceral afferent fibres concerned with the non-sensory aspects of visceral afferent function. Noxious stimulation of viscera activates a variety of specific and non-specific receptors, the vast majority of which are connected to unmyelinated afferent fibres. Studies on the mechanisms of visceral sensation can thus provide information on the more general functions of unmyelinated afferent fibres. Specific visceral nociceptors have been found in the heart, lungs, testes and biliary system, whereas noxious stimulation of the gastro-intestinal tract appears to be detected mainly by non-specific visceral receptors that use an intensity-encoding mechanism. Visceral nociceptive messages are conveyed to the spinal cord by relatively few visceral afferent fibres which activate many central neurons by extensive functional divergence through polysynaptic pathways. Impulses in visceral afferent fibres excite spinal cord neurons also driven by somatic inputs from the corresponding dermatome (viscero-somatic neurons). Noxious intensities of visceral stimulation are needed to activate viscero-somatic neurons, most of which can also be excited by noxious stimulation of their somatic receptive fields. The visceral input to some viscero-somatic neurons in the spinal cord can be mediated via long supraspinal loops. Pathways of projection of viscero-somatic neurons include the spino-reticular and spino-thalamic tracts. All these findings give experimental support to the 'convergence-projection' theory of referred visceral pain. Visceral pain is the consequence of the diffuse activation of somato-sensory nociceptive systems in a manner that prevents accurate spatial discrimination or localization of the stimuli. Noxious stimulation of visceral receptors triggers general reactions of alertness and arousal and evokes unpleasant and poorly localized sensory experiences. This type of response may be a feature of sensory systems dominated by unmyelinated afferent inputs.     

Orexin affects dorsal root ganglion neurons: a mechanism for regulating the spinal nociceptive processing

Orexins (orexin A and B) are initially known to be a hypothalamic peptide critical for feeding and normal wakefulness. In addition, emerging evidence from behavioral tests suggests that orexins are also involved in the regulation of nociceptive processing, suggesting a novel potential therapeutic approach for pain treatment. Both spinal and supraspinal mechanisms appear to contribute to the role of orexin in nociception. In the spinal cord, dorsal root ganglion (DRG) neurons are primary afferent neurons that transmit peripheral stimuli to the pain-processing areas. Morphological results show that both orexin A and orexin-1 receptor are distributed in DRG neurons. Moreover, by using whole-cell patch-clamp recordings and calcium imaging measurements we found that orexin A induced excitability and intracellular calcium concentration elevation in the isolated rat DRG neurons, which was mainly dependent on the activation of spinal orexin-1 receptor. Based on these findings, we propose a hypothesis that the direct effect of orexin A on DRG neurons would represent a possible mechanism for the orexinergic modulation of spinal nociceptive transmission.     

Further characterization of nociception-related and arterial pressure-related neuronal responses in the nucleus reticularis gigantocellularis of the rat

The present study was undertaken to further characterize the nucleus reticularis gigantocellularis (NRGC) of the medulla oblongata in the central processing of nociceptive and cardiovascular signals, and its modulation by metenkephalin. In Sprague-Dawley rats anesthetized with pentobarbital sodium, we found that all 125 spontaneously active NRGC neurons that responded to noxious stimuli (tail clamp) also exhibited arterial pressure-relatedness. Forty neurons additionally manifested cardiac periodicity that persisted even during nociceptive responses. While maintaining their cardiovascular responsive characteristics, the nociception-related NRGC neuronal activity was blocked, naloxone-reversibly (0.5 mg/kg, i.v.), by morphine (5 mg/kg, i.v.). Microiontophoretically applied met-enkephalin suppressed the responsiveness of NRGC neurons to individually delivered tail clamp or transient hypertension induced by phenylephrine (5 µg/kg, i.v.). Interestingly, in NRGC neurons that manifested both nociception and arterial pressure relatedness, the preferential reduction in the response to noxious stimuli upon simultaneous elevation in systemic arterial pressure was reversed to one that favored nociception in the presence of met-enkephalin. All actions of met-enkephalin were discernibly blocked by the opioid receptor antagonist, naloxone. Our results suggest that individual NRGC neurons may participate in the processing of both nociceptive and cardiovascular information, or in the coordination of the necessary circulatory supports during nociception. In addition, neuropeptides such as met-enkephalin may exert differential modulation on neuronal responsiveness according to the prevailing physiologic status of the animal. They also showed that NRGC may be a central integrator for pain and cardiovascular-related functions.