Alan Randich

Role of the right vagal nerve trunk in antinociception

Activation of the cardiopulmonary reflex arc by volume expansion results in antinociception of the tail-flick response to radiant heat, and this antinociception can be attenuated by resection of the right vagal nerve trunk. Resection of the right vagal nerve trunk also attenuates foot-shock induced analgesia ( FSIA ), but this vagal influence appears to be qualitatively different from that produced by volume expansion. These findings indicate that pain perception is modulated by cardiovascular input.

The Role of Sinoaortic and Cardiopulmonary Baroreceptor Reflex Arcs in Nociception and Stress‐Induced Analgesia

Sinoaortic and cardiopulmonary baroreceptor reflex arcs represent the primary mechanisms for maintaining circulatory homeostasis. These arcs utilize both peripheral receptors and central nervous system (CNS) components to control the circulation through reflex adjustments of sympathetic and parasympathetic efferents to the heart and vasculature.1-2 There is also evidence to indicate that peripheral activation of baroreceptor reflex arcs by cardiovascular stimuli concomitantly engages endogenous CNS systems that inhibit pain. It is possible, therefore, that some stress-induced analgesias (SLAs) may be mediated by either stress-induced cardiovascular responses or the stress-induced release of substances that activate these arcs. In our view, at least three different peripheral physiological events are known to occur following the application of experimental stressors that bear upon possible mediation of SIAs by the baroreceptor reflex arcs. These stress-induced events include the release of opioid-like substances into the peripheral circulation, the release of vasoconstrictors, such as norepinephrine, that result in elevations of arterial blood pressure, and changes in the distribution of blood towards the heart, such as during the cardiovascular defense reaction, resulting in increased central blood volume. In the discussion that follows, we will show that hypoalgesia, a diminished sensitivity to tissuedamaging ~t imuli ,~ results from experimental manipulations which can be thought of as modeling these physiological reactions to stress. These manipulations include i.v. administration of [~-Ala~]methionine enkephalinamide, i.v.

Vagal afferent modulation of a nociceptive reflex in rats: involvement of spinal opioid and monoamine receptors

Modulation of the spinal nociceptive tail flick (TF) reflex by electrical stimulation of subdiaphragmatic or cervical vagal afferent fibers was characterized in rats lightly anesthetized with pentobarbital. Cervical vagal afferent stimulation (VAS) inhibited the TF reflex in a pulse width-, frequency-, and intensity-dependent fashion. The optimum parameters for inhibition of the TF reflex were determined to be 2.0 ms pulse width, 20 Hz frequency with a threshold (T) current of 60 microA. Cervical VAS at 0.2-0.6 T facilitated the TF reflex. Cervical VAS at T typically produced a depressor arterial blood pressure response, but inhibition of the TF reflex by VAS was not due to changes in blood pressure. Subdiaphragmatic VAS also inhibited the TF reflex and generally produced a pressor effect, but did not facilitate the TF reflex at intensities of stimulation less than T as did cervical VAS. The parameters of cervical VAS required for inhibition of TF reflex suggest that excitation of high-threshold, unmyelinated fibers are important in VAS-induced descending inhibition. The intrathecal administration of pharmacologic receptor antagonists into the subarachnoid space of the lumbar enlargement indicated that the opioid receptor antagonist naloxone produced a dose-dependent antagonism of cervical VAS-produced inhibition of TF reflex, but single doses of either phentolamine or methysergide (30 micrograms each) failed to affect the inhibition by VAS. Combined intrathecal injection of both phentolamine and methysergide (30 micrograms each), however, significantly attenuated inhibition of the TF reflex by cervical VAS. These results suggest that cervical VAS engages a spinal opioid system and co-activates descending serotonergic and noradrenergic systems to modulate spinal nociceptive processing.

ANTINOCICEPTION AND CARDIOVASCULAR RESPONSES PRODUCED BY INTRAVENOUS MORPHINE : THE ROLE OF VAGAL AFFERENTS

The mechanisms of the antinociceptive, depressor and bradycardic responses produced by intravenous (i.v.) administration of morphine were examined in rats lightly anesthetized with pentobarbital sodium. Intravenous administration of 0.1, 0.25, 0.5, 1.0 or 2.5 mg/kg of morphine produced dose-dependent inhibition of the nociceptive tail flick (TF) reflex, hypotension, and bradycardia. Bilateral cervical vagotomy (CVAG) significantly attenuated the antinociception produced by i.v. morphine and the degree of attenuation was inversely related to drug dose. CVAG had no effect on the depressor response produced by lesser doses of morphine (0.1 or 0.5 mg/kg), but at greater doses converted the depressor response into either a pressor response (1.0 mg/kg) or an initial pressor response followed by a depressor response (2.5 mg/kg). Morphine-induced bradycardia was blocked by CVAG at all drug doses tested (0.1, 0.5, 1.0 and 2.5 mg/kg). In selective tests of either 0.5 or 2.5 mg/kg of i.v. morphine, prior administration of the peripherally acting opioid receptor antagonist naloxone methobromide (NMB) attenuated the antinociception to the same degree as CVAG. NMB also completely blocked the depressor and bradycardic responses of these doses of morphine. Bilateral subdiaphragmatic vagotomy (SDVAG) resulted in a marginal attenuation of antinociception at 0.5 mg/kg but not 2.5 mg/kg of morphine, and the attenuation produced by SDVAG was delayed in onset following morphine administration relative to that produced by CVAG. Bilateral sino-aortic deafferentation (SAD) had no significant effect on the antinociception in tests with 0.5 mg/kg of morphine. SDVAG and SAD had little effect on cardiovascular responses produced by these doses of morphine. The spinal antinociceptive systems activated by vagal afferents following i.v. morphine administration were characterized with the 0.5 mg/kg dose. Spinal cold block significantly antagonized the antinociception, hypotension and bradycardia produced by this dose of morphine. Intrathecal administration of naloxone (1.5, 15 or 30 micrograms) significantly antagonized the antinociception compared to saline controls, whereas intrathecal administration of methysergide (30 micrograms), phentolamine (30 micrograms), or the combination of methysergide with phentolamine (30 micrograms each) had no significant effect on the antinociception. These intrathecal doses of naloxone also antagonized the depressor and bradycardic responses produced by morphine. However, the antagonism produced by 1.5 micrograms of intrathecal naloxone was not due to spread to the systemic circulation, since i.v. administration of 1.5 micrograms of naloxone did not significantly affect either the antinociceptive or cardiovascular responses produced by morphine. These findings indicate that vagal afferents play a significant role in the antinociception produced by i.v. administration of morphine.(ABSTRACT TRUNCATED AT 400 WORDS)

Antinociception and cardiovascular responses produced by electrical stimulation in the nucleus tractus solitarius, nucleus reticularis ventralis, and the caudal medulla

&NA; In experiment 1, quantitative regional comparisons of the antinociceptive and cardiovascular responses produced by electrical stimulation in the caudal medulla, including regions such as the nucleus tractus solitarius (NTS), nucleus reticularis ventralis (NRV), nucleus reticularis gigantocellularis (NRGC), nucleus reticularis paragigantocellularis (NRPGC), nucleus raphe obscurus (NRO), and medial portions of the lateral reticular nucleus (LRN), were made in the rat. Electrical stimulation in all of these regions resulted in inhibition of the nociceptive tail‐flick reflex, although the threshold intensity for inhibition was greater for sites in NTS compared to many sites ventral to the NTS. Antinociception was generally accompanied by an increase in mean arterial blood pressure, with the exception of sites in the NRO, where depressor responses were evoked by stimulation. Detailed comparisons between the NTS and NRV revealed that greater intensities of electrical stimulation were required to produce antinociception for sites in the NTS as compared to the NRV. There were no significant differences in threshold intensities for antinociception as a function of rostrocaudal subdivisions of the NTS, but the lateral subdivision of the NTS was significantly more efficacious than the medial subdivision. This mediolateral difference within NTS was primarily due to stimulation in medial sites producing overt movements in some animals, probably due to stimulation of adjacent midline nuclei or pathways. Within the NRV, thresholds for inhibition of the tail‐flick reflex were greater for sites in the dorsal subdivision as compared to the ventral subdivision, which contains spinopetal projections from the NRM. The slopes of the lines of recruitment for inhibition of the tail‐flick reflex at stimulation sites in either the NTS or NRV were both very steep, similar to other forms of antinociception. In experiment 2, the pulse duration of electrical stimulation was varied for sites of stimulation in the lateral NTS and NRV to generate strength‐duration curves. This experiment confirmed that stimulation sites in the lateral NTS required greater current intensities to inhibit the tail‐flick reflex than sites in the NRV. However, the chronaxies derived from the strength‐duration functions for the NTS or NRV were both approximately 170 &mgr;sec, indicating that the antinociceptive effects in these regions may not be exclusively due to the stimulation of fibers of passage. These results are discussed in terms of the role of the NTS, NRV, and caudal medulla in the modulation of nociceptive responses and cardiovascular function.

Medullary substrates mediating antinociception produced by electrical stimulation of the vagus

Electrical stimulation of afferents of the right cervical vagus inhibited the tail-flick reflex elicited by noxious heat in barbiturate-anesthetized rats. This inhibitory effect was eliminated in rats receiving local anesthetic blockade of either the nucleus tractus solitarii (NTS), the lateral reticular nuclei, the nucleus raphe magnus-medullary reticular formation, or nucleus raphe obscurus regions of the medulla. Similarly, the vasodepressor and bradycardic effects of vagal stimulation were either attenuated or eliminated by local anesthetic blockade of these regions. Microinjection of the non-specific glutamate antagonist gamma-D-glutamylglycine (DGG) into the NTS region also eliminated vagally evoked inhibition of the tail-flick reflex, hypotension, and bradycardia. Conversely, microinjection of glutamate into the NTS region resulted in inhibition of the tail-flick reflex, hypotension, and bradycardia. These findings with DGG and glutamate are consistent with the view that glutamate serves as a neurotransmitter of the primary vagal afferents mediating these antinociceptive and cardiovascular responses. These results are discussed in terms of vagal afferent influences on somatosensory, somatomotor, and cardiovascular function.

Effects of electrical stimulation of vagal afferents on spinothalamic tract cells in the rat

&NA; The effects of electrical stimulation of cervical vagal afferents (VAS) on the background activity and on the responses of 25 spinothalamic tract (STT) neurons to noxious stimuli were studied in anesthetized rats. Background (spontaneous) activity of 9 (36%) STT neurons was inhibited by all intensities of VAS, 6 (24%) units were facilitated at lesser and inhibited at greater intensities of VAS, 5 (20%) units were only facilitated by all intensities of VAS, and 5 (20%) units were not affected by VAS. Responses of 8 (36%) STT neurons to noxious stimuli were only inhibited by VAS, 9 (41%) were facilitated at lesser and inhibited at greater intensities of VAS, and 5 units (23%) were only facilitated by VAS. There were no significant differences in VAS‐produced modulatory effects between STT neurons and 16 unidentified lumbar spinal dorsal horn neurons studied under the same conditions. These results reveal that descending facilitatory and inhibitory pathways engaged by activation of vagal afferents modulate rostrally projecting nociceptive transmission neurons in the spinal cord, constituting an important regulatory network for nociception.

[D-Ala2]-methionine enkephalinamide reflexively induces antinociception by activating vagal afferents

Experiment 1 showed that intravenous administration of [D-Ala2]-methionine enkephalinamide resulted in dose-dependent inhibition of the tail-flick reflex, mild hypotension, and bradycardia. The enkephalinamide-induced inhibition of the tail-flick reflex and cardiovascular effects were eliminated in the bilateral cervical vagotomized anesthetized rat preparation, but were unaffected by either a unilateral right vagotomy or bilateral sinoaortic deafferentation in the conscious rat preparation. Experiment 2 demonstrated that the antinociceptive and cardiovascular actions of enkephalinamide were eliminated by pretreatment with intravenous administration of the opioid-receptor antagonist naloxone. These experiments strongly suggest that peripherally circulating enkephalins could reflexively induce analgesia by activating cardiopulmonary receptors whose afferents travel in the vagi.

Acute increases in arterial blood pressure produced by occlusion of the abdominal aorta induces antinociception: peripheral and central substrates

Occlusion of the abdominal aorta proximal to the renal arteries results in an increase in arterial blood pressure, inhibition of forepaw and hindpaw withdrawal to a noxious mechanical stimulus, and inhibition of the tail-flick reflex to noxious heat. Occlusion of the abdominal aorta distal to the renal arteries does not elevate arterial blood pressure and produces no antinociceptive effects. Occlusion of the vena cava lowers arterial blood pressure and produces no antinociception. The inhibitory effects of occlusion of the abdominal aorta depend upon activation of high pressure baroreceptors since bilateral sinoaortic denervation, but not bilateral vagotomy, eliminates the inhibition with respect to all behavioral measures. The inhibitory effects with respect to the tail-flick reflex also depend upon activation of a descending inhibitory system since reversible cold block of the spinal cord at the level of the second thoracic vertebra eliminates the antinociception. This antinociception is also eliminated following intrathecal administration of the noradrenergic receptor antagonist phentolamine, but not by intrathecal administration of either methysergide or naloxone. These data support the view that activation of high pressure baroreceptors by increases in arterial blood pressure produces antinociception via activation of a spinopetal noradrenergic system.

The US preexposure phenomenon in the conditioned suppression paradigm: A role for conditioned situational stimuli ☆

Abstract Four experiments evaluated possible associative and nonassociative accounts of the retardation in the acquisition of conditioned suppression produced by repeated prior exposure to an electric shock US. Associative interference resulting from conditioning of situational stimuli during preexposure to shock was suggested by the findings that signaling the occurrence of high-intensity shock with a discrete nontarget CS during the preexposure phase reduced the magnitude of the retardation effect compared to an unsignaled shock preexposure treatment (Experiments 1 and 4), nonreinforced presentations of putatively conditioned situational stimuli prior to conditioned suppression training reduced the magnitude of the retardation effect (Experiment 2), and the magnitude of the retardation effect was directly related to the intensity of preexposure shock (Experiment 3). Nonassociative interference was suggested by the finding that signaling the occurrence of low-intensity shock with a discrete nontarget CS during the preexposure phase did not reduce the magnitude of the retardation effect compared to an unsignaled shock preexposure treatment (Experiment 4). It was suggested that associative and nonassociative mechanisms govern the US preexposure phenomenon obtained in the conditioned suppression paradigm, and their relative contribution depends upon the intensity of shock.