The study of pain in awake animals raises ethical, philosophical, and technical problems. We review the ethical standards for studying pain in animals and emphasize that there are scientific as well as moral reasons for keeping to them. Philosophically, there is the problem that pain cannot be monitored directly in animals but can only be estimated by examining their responses to nociceptive stimuli; however, such responses do not necessarily mean that there is a concomitant sensation. The types of nociceptive stimuli (electrical, thermal, mechanical, or chemical) that have been used in different pain models are reviewed with the conclusion that none is ideal, although chemical stimuli probably most closely mimic acute clinical pain. The monitored reactions are almost always motor responses ranging from spinal reflexes to complex behaviors. Most have the weakness that they may be associated with, or modulated by, other physiological functions. The main tests are critically reviewed in terms of their sensitivity, specificity, and predictiveness. Weaknesses are highlighted, including 1) that in most tests responses are monitored around a nociceptive threshold, whereas clinical pain is almost always more severe; 2) differences in the fashion whereby responses are evoked from healthy and inflamed tissues; and 3) problems in assessing threshold responses to stimuli, which continue to increase in intensity. It is concluded that although the neural basis of the most used tests is poorly understood, their use will be more profitable if pain is considered within, rather than apart from, the body's homeostatic mechanisms.

Animal Models of Nociception

The sympathetic nervous system is an important regulator of blood pressure Guyenet describes the central control regions that influence the activity of sympathetic efferent neurons and their potential contribution to neurogenic hypertension Hypertension — the chronic elevation of blood pressure — is a major human health problem In most cases, the root cause of the disease remains unknown, but there is mounting evidence that many forms of hypertension are initiated and maintained by an elevated sympathetic tone This review examines how the sympathetic tone to cardiovascular organs is generated, and discusses how elevated sympathetic tone can contribute to hypertension

The sympathetic control of blood pressure

Methods and apparatus are provided for renal neuromodulation using a pulsed electric field to effectuate electroporation or electrofusion. It is expected that renal neuromodulation (e.g., denervation) may, among other things, reduce expansion of an acute myocardial infarction, reduce or prevent the onset of morphological changes that are affiliated with congestive heart failure, and/or be efficacious in the treatment of end stage renal disease. Embodiments of the present invention are configured for percutaneous intravascular delivery of pulsed electric fields to achieve such neuromodulation.

Methods and apparatus for renal neuromodulation

We have attempted in this review to give an account of an afferent vagal input from the lower respiratory tract that has still to be explored fully, and to present experimental evidence that this fine fibre afferent system plays a significant role in the neural control of respiratory function in both normal and pathological circumstances.

Afferent vagal C fibre innervation of the lungs and airways and its functional significance

A method and apparatus for treatment of heart failure, hypertension and renal failure by stimulating the renal nerve. The goal of therapy is to reduce sympathetic activity of the renal nerve. Therapy is accomplished by at least partially blocking the nerve with drug infusion or electrostimulation. Apparatus can be permanently implanted or catheter based.

Renal nerve stimulation method and apparatus for treatment of patients

The baroreceptor reflex has been found to be attenuated during anesthesia, but the effects of the relatively new anesthetic, isoflurane, on baroreflex function have not been examined thoroughly. This study was performed to determine the effects of isoflurane on each component of the baroreceptor reflex arc, including the receptors, afferent and efferent nerve pathways, central integratory centers, peripheral ganglia, and the heart. Baroreflex effects on heart rate initiated by systemic pressure changes were examined in conscious and anesthetized dogs (1.3% and 2.6% isoflurane). The effects on individual components of the reflex arc were determined by examining carotid sinus baroreceptor afferent activity, sympathetic efferent nerve activity, and heart rate response to direct sympathetic and parasympathetic efferent nerve stimulation in anesthetized dogs. Preganglionic and postganglionic nerve activities were recorded simultaneously during baroreflex activation to determine ganglionic effects of isoflurane. Baroreflex-induced changes in heart rate were not depressed significantly until 2.6% isoflurane if blood pressure changes due to anesthetic administration were prevented. Significant decreases in baseline sympathetic efferent nerve activity were found at 1.3% and 2.6% isoflurane, with depression of postganglionic activity significantly greater than preganglionic activity at 2.6% isoflurane, indicating a ganglionic effect of isoflurane. Cardiac chronotropic responses to direct stimulation of sympathetic and vagal fibers were attenuated significantly by isoflurane, with sympathetic stimulation showing the greater sensitivity to the anesthetic. Carotid baroreceptor afferent activity was increased by isoflurane, and this sensitization of the baroreceptors appeared to contribute to the decreased levels of sympathetic tone. Therefore, although isoflurane was found to alter the baroreceptor reflex through its effects at multiple sites of the baroreflex arc, significant depression of the cardiac chronotropic component of the reflex was seen only at 2.6% isoflurane.

Effects of Isoflurane on the Baroreceptor Reflex

Baroreceptor reflexes have been found to be attenuated during halothane anesthesia in humans and experimental animals. The baroreceptor reflex arc is comprised for a number of components, including receptors, afferent and efferent nerve pathways, central integratory centers, peripheral ganglia, and effector organs, at which halothane might exert an inhibitory effect. This study was performed to determine the effect of halothane at each component in order to identify the site or sites of baroreflex attenuation due to halothane. The baroreflex effects on heart rate initiated by carotid sinus pressure changes were examined in conscious and anesthetized (0.0%, 0.75%, and 1.5% halothane in 50% N2O and O2, pls 25 mg/kg thiopental) dogs. In addition, carotid sinus afferent activity, cardiac sympathetic efferent activity and heart responses to direct sympathetic and parasympathetic efferent stimulation were examined in anesthetized dogs. Preganglionic and postganglionic sympathetic nerve activities were recorded simultaneously during baroreceptor activation to determine ganglionic effects of halothane. All levels of anesthesia significantly (P less than 0.05) attenuated reflex changes in heart rate produced by the pressure changes compared to conscious dogs. Significant decreases in cardiac sympathetic efferent activity were produced at 1.5% halothane (P less than 0.05). The depression in postganglionic activity was significantly greater than that or preganglionic activity, indicating a ganglionic-blocking effect by halothane. Cardiac chronotropic changes produced by direct efferent stimulation of sympathetic and vagal fibers were attenuated significantly by halothane (P less than 0.05). On the other hand, baroreceptor afferent activity was increased at 1.5% halothane. This sensitization of baroreceptors appeared to contribute to decreased levels of sympathetic tone, leading to blunted reflex changes in nerve activity. Therefore, halothane was found to have multiple sites of action, leading to depression of the baroreflex.

Halothane and the carotid sinus reflex: evidence for multiple sites of action.

Activation of carotid sinus (CS) baroreceptors has been shown to increase inspiratory time (Ti) and expiratory time (Te) and to have a varied effect on tidal volume. The contribution of two functio...

Respiratory responses to selective blockade of carotid sinus baroreceptors in the dog

The hypotension accompanying isoflurane suggests that the anesthetic produces an attenuation of sympathetic tone. Previous studies examining the effects of isoflurane on sympathetic efferent nerve activity have required concomitant use of a basal anesthetic or decerebration, both of which independently alter sympathetic activity. This study was performed to examine the effects of isoflurane on sympathetic efferent nerve activity in the absence of basal anesthetic or decerebration. Five mongrel dogs were anesthetized with 4% isoflurane by mask. Platinum electrodes chronically were implanted around a renal nerve adjacent to the renal artery in order to measure renal sympathetic efferent nerve activity in the conscious and anesthetized animal. After 5-24 h for recovery, renal nerve activity and arterial pressure (via an implanted femoral artery cannula) were measured in the conscious, resting animal (control); during induction (4% isoflurane) and intubation; in the anesthetized animal (1.5% and 2.5% isoflurane); and during recovery and extubation. Isoflurane produced a significant dose-dependent depression of arterial blood pressure but did not significantly change heart rate from control. Renal sympathetic efferent nerve activity at 1.5% isoflurane was not significantly different from that in conscious animals, but nerve activity at 2.5% isoflurane was depressed significantly from both control and 1.5% isoflurane. Both intubation and extubation were accompanied by an increase in sympathetic nerve activity. Isoflurane appeared to directly depress sympathetic activity at both levels of anesthesia, but the direct depression of activity at 1.5% isoflurane seemed to be countered by reflex increases in sympathetic tone due to the hypotension accompanying the anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Sympathetic efferent nerve activity in conscious and isoflurane-anesthetized dogs.

A rise in arterial blood pressure can be evoked by microinjections of d,l -homocysteic acid into localized regions of the ventrolateral medulla of the cat. Three patterns of sympathetic discharge can be identified during the pressor response. A differential pattern consisting of an increase in renal nerve activity and no change in sympathetic activity to skeletal muscle vasculature can be elicited from sites ventromedial to the caudal pole of the facial nucleus. From more lateral and caudal sites, a generalized sympatho-excitation is evoked in the outflow to both the kidney and hindlimb muscle vasculature. A third response consisting of a differential increase in muscle sympathetic activity simultaneous with a small decrease in renal nerve activity could be evoked from caudal sites, lateral to the inferior olives and superficial to the ventral surface. The results show that ventral medullary neurons can selectively activate sympathetic outflow to control specific vascular beds. These data may support the hypothesis that the ventrolateral medulla contains discrete groups of topographically arranged neurons that can differentially control sympathetic tone to various end-organs.

F. A. Hopp

Papers

Effects of Isoflurane on the Baroreceptor Reflex

Halothane and the carotid sinus reflex: evidence for multiple sites of action.

Respiratory responses to selective blockade of carotid sinus baroreceptors in the dog

Sympathetic efferent nerve activity in conscious and isoflurane-anesthetized dogs.

Differential control of sympathetic activity to kidney and skeletal muscle by ventral medullary neurons.