Anesthetic effects on fictive locomotion in the rat isolated spinal cord.

General anesthetic mechanisms are poorly understood. Anesthetic immobilizing effects occur in the spinal ventral horn. However, a detailed analysis of anesthetic effects on ventral motor networks is lacking.

Validation and insights of anesthetic action in an early vertebrate network: the isolated lamprey spinal cord.

Background: The lamprey spinal cord is a well-characterized vertebrate network that could facilitate our understanding of anesthetic action. We tested several hypotheses concerning the lamprey's clinical application to anesthesia, and the sites/mechanisms of anesthetic action.

Methods: In isolated lamprey spinal cords, minimum immobilizing concentrations (MICs) were determined for halothane, isoflurane, sevoflurane, desflurane, propofol, or the nonimmobilizer F6 (1,2-dichlorohexafluorocyclobutane), applied during D-glutamate-induced fictive swimming or noxious tail stimulation.

Analgesia mediated by soluble epoxide hydrolase inhibitors is dependent on cAMP.

Pain is a major health concern even though numerous analgesic agents are available. Side effects and lack of wide-spectrum efficacy of current drugs justify efforts to better understand pain mechanisms. Stabilization of natural epoxy-fatty acids (EFAs) through inhibition of the soluble epoxide hydrolase (sEH) reduces pain.

Naturally occurring monoepoxides of eicosapentaenoic acid and docosahexaenoic acid are bioactive antihyperalgesic lipids.

Beneficial physiological effects of long-chain n-3 polyunsaturated fatty acids are widely accepted but the mechanism(s) by which these fatty acids act remains unclear. Herein, we report the presence, distribution, and regulation of the levels of n-3 epoxy-fatty acids by soluble epoxide hydrolase (sEH) and a direct antinociceptive role of n-3 epoxy-fatty acids, specifically those originating from docosahexaenoic acid (DHA). The monoepoxides of the C18:1 to C22:6 fatty acids in both the n-6 and n-3 series were prepared and the individual regioisomers purified.

Dorsal horn neurons expressing NK-1 receptors mediate scratching in rats.

Itch is thought to be signaled by pruritogen-responsive neurons in the superficial spinal dorsal horn. Many neurons here express the substance P NK-1 receptor. We investigated whether neurotoxic destruction of spinal NK-1-expressing neurons affected itch-related scratching behavior.

Brainstem regions affecting minimum alveolar concentration and movement pattern during isoflurane anesthesia.

Background: Spinal transection or selective delivery of volatile anesthetics to the spinal cord reduces minimum alveolar concentration (MAC), whereas precollicular decerebration does not. The authors sought to determine which brainstem regions influence anesthetic requirements and movement responses with isoflurane.

Methods: Movement (biceps femoris electromyogram) and MAC were measured in adult rats before and after decerebration at the precollicular, mid-collicular, pontine or medullary level, or decerebellation.

Nitrous oxide-induced analgesia does not influence nitrous oxide's immobilizing requirements.

Background: Nitrous oxide (N(2)O) acts on supraspinal noradrenergic neurons to produce analgesia, but it is unclear if analgesia contributes to N(2)O's immobilizing effects. We tested the hypothesis that N(2)O minimum alveolar anesthetic concentration (MAC) is unchanged after selective ablation of supraspinal noradrenergic neurons, or in naïve animals at N(2)O exposure timepoints when analgesia is absent.

Methods: We determined tailflick latency (TFL) and hindpaw withdrawal latency (HPL) under 70% N(2)O, N(2)O MAC, and isoflurane MAC before and after intracerebroventricular injections of anti-dopamine-beta hydroxylase conjugated to saporin (SAP-DBH; n = 7), or a control antibody conjugated to saporin (n = 5).

Rat dorsal horn nociceptive-specific neurons are more sensitive than wide dynamic range neurons to depression by immobilizing doses of volatile anesthetics: an effect partially reversed by the opioid receptor antagonist naloxone.

Background: The mechanism and site of action within the spinal cord by which volatile anesthetics produce immobility are not well understood. Little work has been done directly comparing anesthetic effects on neurons with specific functional characteristics that mediate transfer of nociceptive information within the spinal cord.

Methods: Adult male rats were anesthetized and prepared for extracellular single-unit recordings from the lumbar dorsal horn.

Propofol produces immobility via action in the ventral horn of the spinal cord by a GABAergic mechanism.

Background: We investigated the actions of propofol and isoflurane on nociceptive responses of neurons in the spinal cord.

Methods: We determined nociceptive responses of lumbar neurons in the dorsal horn (<1200 microm) and ventral horn (>1200 microm) of decerebrate rats before and during propofol (1 effective dose, ED(50)) or isoflurane (1 minimum alveolar concentration) anesthesia. During recording of ventral horn neurons, we administered picrotoxin by infusion to determine whether isoflurane and propofol differed in their effects at the gamma aminobutyric acid (GABA) Type A receptors.

Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways.

During inflammation, a large amount of arachidonic acid (AA) is released into the cellular milieu and cyclooxygenase enzymes convert this AA to prostaglandins that in turn sensitize pain pathways. However, AA is also converted to natural epoxyeicosatrienoic acids (EETs) by cytochrome P450 enzymes. EET levels are typically regulated by soluble epoxide hydrolase (sEH), the major enzyme degrading EETs.

Increases in spinal cerebrospinal fluid potassium concentration do not increase isoflurane minimum alveolar concentration in rats.

Background: Previous studies demonstrated that MAC for isoflurane directly correlates with the concentration of Na(+) in cerebrospinal fluid surrounding the spinal cord, the primary site for mediation of the immobility produced by inhaled anesthetics. If this correlation resulted from increased irritability of the cord, then infusion of increased concentrations of potassium (K(+)) might be predicted to act similarly. However, an absence of effect of K(+) might be interpreted to indicate that K(+) channels do not mediate the immobility produced by inhaled anesthetics whereas Na(+) channels remain as potential mediators.

The effects of aromatic anesthetics on dorsal horn neuronal responses to noxious stimulation.

Background: Gamma-aminobutyric acid type A receptor potentiation and/or N-methyl-d-aspartate (NMDA) receptor inhibition might explain the anesthetic properties of fluorinated aromatic compounds. We hypothesized that depression of dorsal horn neuronal responses to noxious stimulation would correlate with the magnitude of effect of benzene (BNZ), o-difluorobenzene, and hexafluorobenzene (HFB) on NMDA receptors.

Methods: Rats were anesthetized with desflurane.

Volatile anesthetic effects on midbrain-elicited locomotion suggest that the locomotor network in the ventral spinal cord is the primary site for immobility.

Background: Volatile anesthetics produce immobility primarily by action in the spinal cord; however, anesthetic effects among different neuronal classes located in different spinal regions, and how they relate to immobility, are not understood.

Methods: In decerebrated rats, effects of isoflurane and halothane on movement elicited by electrical microstimulation of the mesencephalic locomotor region (MLR) were assessed in relation to minimum alveolar concentration (MAC). Anesthetic effects on step frequency and isometric limb force were measured.

Immobilizing doses of halothane, isoflurane or propofol, do not preferentially depress noxious heat-evoked responses of rat lumbar dorsal horn neurons with ascending projections.

Background: The spinal cord is an important site where volatile anesthetics decrease sensation and produce immobility. Beyond this knowledge, our understanding of a site of anesthetic action is limited. Previous evidence suggests that dorsal horn neurons with ascending projections may be more susceptible to depression by general anesthetics than local spinal interneurons.

Glutamate receptor blockade in the rostral ventromedial medulla reduces the force of multisegmental motor responses to supramaximal noxious stimuli.

The rostral ventromedial medulla (RVM) has been established as part of a descending pain-modulatory pathway. While the RVM has been shown to modulate homosegmental nociceptive reflexes such as tail flick or hindpaw withdrawal, it is not known what role the RVM plays in modulating the magnitude of multisegmental, organized motor responses elicited by noxious stimuli. Using local blockade of glutamate receptors with the non-specific glutamate receptor antagonist kynurenate (known to selectively block nociceptive facilitatory ON-cells), we tested the hypothesis that the RVM facilitates the magnitude of multi-limb movements elicited by intense noxious stimuli.

Neurons in the ventral spinal cord are more depressed by isoflurane, halothane, and propofol than are neurons in the dorsal spinal cord.

Background: Volatile anesthetics act primarily in the spinal cord to produce immobility but their exact site of action is unclear. Between 0.8 and 1.

Soluble epoxide hydrolase inhibition reveals novel biological functions of epoxyeicosatrienoic acids (EETs).

Early on, intriguing biological activities were found associated with the EETs using in vitro systems. Although the EETs other than the 5,6-isomer, are quite stable chemically, they are quickly degraded enzymatically with the sEH accounting in many cases for much of the metabolism. This rapid degradation often made it difficult to associate biological effects with the administration of EETs and other lipid epoxides particularly in vivo.

Inhibition of soluble epoxide hydrolase reduces LPS-induced thermal hyperalgesia and mechanical allodynia in a rat model of inflammatory pain.

Soluble epoxide hydrolases catalyze the hydrolysis of epoxides in acyclic systems. In man this enzyme is the product of a single copy gene (EPXH-2) present on chromosome 8. The human sEH is of interest due to emerging roles of its endogenous substrates, epoxygenated fatty acids, in inflammation and hypertension.

Enhancement of antinociception by coadministration of nonsteroidal anti-inflammatory drugs and soluble epoxide hydrolase inhibitors.

Combination therapies have long been used to treat inflammation while reducing side effects. The present study was designed to evaluate the therapeutic potential of combination treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and previously undescribed soluble epoxide hydrolase inhibitors (sEHIs) in lipopolysaccharide (LPS)-challenged mice. NSAIDs inhibit cyclooxygenase (COX) enzymes and thereby decrease production of metabolites that lead to pain and inflammation.

Nitrous oxide depresses electroencephalographic responses to repetitive noxious stimulation in the rat.

Background: Although N(2)O has been widely used as an anaesthetic adjuvant its effect on electroencephalographic (EEG) activity is poorly understood because it is usually studied in the presence of additional anaesthetics, including inhaled anaesthetics. We examined the EEG effects of N(2)O in rats using a hyperbaric chamber that permitted N(2)O to be the sole anaesthetic.

Methods: Rats (n=10) were anaesthetized with isoflurane and EEG activity was recorded from skull screws.

Drastic decrease in isoflurane minimum alveolar concentration and limb movement forces after thoracic spinal cooling and chronic spinal transection in rats.

Background: Individuals with spinal cord injury may undergo multiple surgical procedures; however, it is not clear how spinal cord injury affects anesthetic requirements and movement force under anesthesia during both acute and chronic stages of the injury.

Methods: The authors determined the isoflurane minimum alveolar concentration (MAC) necessary to block movement in response to supramaximal noxious stimulation, as well as tail-flick and hind paw withdrawal latencies, before and up to 28 days after thoracic spinal transection. Tail-flick and hind paw withdrawal latencies were measured in the awake state to test for the presence of spinal shock or hyperreflexia.

Isoflurane depresses windup of C fiber-evoked limb withdrawal with variable effects on nociceptive lumbar spinal neurons in rats.

Windup is a progressive increase in responses of nociceptive spinal cord neurons to repeated electrical C fiber stimulation. We hypothesized that isoflurane would depress windup at approximately the minimum alveolar anesthetic concentration (MAC) required to suppress purposeful movement in response to noxious stimulation. We recorded windup responses in single lumbar spinal neurons (n = 17) to a series of 15 repetitive electrical stimuli delivered at 1 Hz to the hindpaw at C fiber strength; hindpaw withdrawal force was simultaneously recorded.

A model for differential volatile anesthetic delivery to the upper and lower torso of the rabbit.

Introduction: We have developed a model that permits differential delivery of volatile anesthetics to the upper and lower torso of the rabbit.

Methods: Rabbits were anesthetized with isoflurane (n = 4) or halothane (n = 3), and blood was drained from a carotid cannula into a membrane oxygenator and reinfused via a renal artery cannula into the lower torso circulation using a roller pump. Bypass of the lower torso circulation was achieved by tightening a ligature around the aorta at the level of the renal arteries.