The Analgesic Action of Nitrous Oxide Is Dependent on the Release of Norepinephrine in the Dorsal Horn of the Spinal Cord 

1999 ◽  
Vol 91 (5) ◽  
pp. 1401-1401 ◽  
Author(s):  
Chousheng Zhang ◽  
Frances M. Davies ◽  
Tian-Zhi Guo ◽  
Mervyn Maze
Keyword(s):  
Spinal Cord ◽  
Nitrous Oxide ◽  
Dorsal Horn ◽  
Opiate Receptors ◽  
Periaqueductal Gray ◽  
Separate Experiment ◽  
Tail Flick ◽  
Fourfold Increase ◽  
Noradrenergic Pathway ◽  
Analgesic Response

Background The authors and others have demonstrated that supraspinal opiate receptors and spinal alpha2 adrenoceptors are involved in the analgesic mechanism for nitrous oxide (N2O). The authors hypothesize that activation of opiate receptors in the periaqueductal gray results in the activation of a descending noradrenergic pathway that releases norepinephrine onto alpha2 adrenoceptors in the dorsal horn of the spinal cord. Methods The spinal cord was transected at the level of T3-T4 in rats and the analgesic response to 70% N2O in oxygen was determined by the tail flick latency test. In a separate experiment in rats a dialysis fiber was positioned transversely in the dorsal horn of the spinal cord at the T12 level. The following day, the dialysis fiber was infused with artificial cerebrospinal fluid at a rate of 1.3 microl/min, and the effluent was sampled at 30-min intervals. After a 60-min equilibration period, the animals were exposed to 70% N2O in oxygen. The dialysis experiment was repeated in animals that were pretreated with naltrexone (10 mg/kg, intraperitoneally) before N2O. In a third series, spinal norepinephrine was depleted with n-(2-chloroethyl)-n-ethyl-2-bromobenzylamine (DSP-4), and the analgesic response to 70% N2O in oxygen was determined. Results The analgesic effect of N2O was prevented by spinal cord transection. After exposure to N2O, there was a fourfold increase in norepinephrine released in the first 30-min period, and norepinephrine was still significantly elevated after 1 h of exposure. The increased norepinephrine release was prevented by previous administration of naltrexone. Depletion of norepinephrine in the spinal cord blocked the analgesic response to N2O. Conclusions A descending noradrenergic pathway in the spinal cord links N2O-induced activation of opiate receptors in the periaqueductal gray, with activation of alpha2 adrenoceptors in the spinal cord. N2O-induced release of norepinephrine in the dorsal horn of the spinal cord is blocked by naltrexone, as is the analgesic response. Spinal norepinephrine is necessary for the analgesic response to the N2O.

scholarly journals Xenon Has Greater Inhibitory Effects on Spinal Dorsal Horn Neurons than Nitrous Oxide in Spinal Cord Transected Cats

1999 ◽  
Vol 88 (4) ◽  
pp. 893-897 ◽  
Author(s):  
Yoshiya Miyazaki ◽  
Takehiko Adachi ◽  
Jun Utsumi ◽  
Tsutomu Shichino ◽  
Hajime Segawa
Keyword(s):  
Spinal Cord ◽  
Nitrous Oxide ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Inhibitory Effects ◽  
Dorsal Horn Neurons ◽  
Spinal Dorsal ◽  
Spinal Dorsal Horn Neurons

Dexmedetomidine Enhances Analgesic Action of Nitrous Oxide

2004 ◽  
Vol 100 (4) ◽  
pp. 894-904 ◽  
Author(s):  
Cecilia Dawson ◽  
Daqing Ma ◽  
Andre Chow ◽  
Mervyn Maze
Keyword(s):  
Spinal Cord ◽  
Nitrous Oxide ◽  
Neuronal Activity ◽  
Locus Ceruleus ◽  
Tail Flick ◽  
Receptor Subtypes ◽  
Dental Surgery ◽  
Analgesic Effects ◽  
Adrenoceptor Antagonist ◽  
Tail Flick Latency

Background Nitrous oxide and dexmedetomidine are thought to mediate analgesia (antinociception in a noncommunicative organism) via alpha 2B- and alpha 2A-adrenergic receptor subtypes within the spinal cord, respectively. Nitrous oxide and dexmedetomidine exert diametrically opposite effects on neuronal activity within the locus ceruleus, a pivotal site for modulation of analgesia. Because of these differences, the authors explored whether the two analgesics in combination would provide satisfactory analgesia. Methods The analgesic effects of nitrous oxide and dexmedetomidine given both intraperitoneally and intrathecally were evaluated using the tail-flick latency test in rats. For investigation of the interaction, rats were pretreated with dexmedetomidine, either intraperitoneally or intrathecally, immediately before nitrous oxide exposure such that peak antinociceptive effects of each drug coincided. For assessment of the effect on tolerance, dexmedetomidine was administered as tolerance to nitrous oxide developed. Expression of c-Fos was used to assess neuronal activity in the locus ceruleus. Results Nitrous oxide and dexmedetomidine increased tail-flick latency with an ED50 (mean +/- SEM) of 55.0 +/- 2.2% atm for nitrous oxide, 27.6 +/- 5.1 for microg/kg intraperitoneal dexmedetomidine, and 2.9 +/- 0.1 microg for intrathecal dexmedetomidine. Combinations of systemically administered dexmedetomidine and nitrous oxide produced an additive analgesic interaction; however, neuraxially administered dexmedetomidine interacted synergistically with nitrous oxide. Tolerance to nitrous oxide was reversed by coadministration of dexmedetomidine. Prazosin, the alpha 1-/alpha 2B-adrenoceptor antagonist, attenuated the analgesic effect of nitrous oxide and prevented dexmedetomidine-induced reversal of tolerance to nitrous oxide. Nitrous oxide-induced increase of neuronal activity in the locus ceruleus was reversed by dexmedetomidine. Conclusion The synergistic analgesic interaction between nitrous oxide and dexmedetomidine within the spinal cord is obscured by a supraspinal antagonism when dexmedetomidine is administered systemically in the pretolerant state. After tolerance to nitrous oxide develops, supraspinal functional antagonism no longer obtains exposing the synergistic action at the level of the spinal cord, which expresses itself as a reversal of the tolerant state. The authors speculate that the addition of dexmedetomidine to nitrous oxide is likely to provide enhanced and more durable analgesia in settings in which nitrous oxide is currently used alone (e.g., labor and dental surgery).

scholarly journals Xenon Has Greater Inhibitory Effects on Spinal Dorsal Horn Neurons than Nitrous Oxide in Spinal Cord Transected Cats

1999 ◽  
Vol 88 (4) ◽  
pp. 893-897 ◽  
Author(s):  
Yoshiya Miyazaki ◽  
Takehiko Adachi ◽  
Jun Utsumi ◽  
Tsutomu Shichino ◽  
Hajime Segawa
Keyword(s):  
Spinal Cord ◽  
Nitrous Oxide ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Inhibitory Effects ◽  
Dorsal Horn Neurons ◽  
Spinal Dorsal ◽  
Spinal Dorsal Horn Neurons

Nitrous Oxide Produces Antinociceptive Response via α2Band/or α2CAdrenoceptor Subtypes in Mice 

1999 ◽  
Vol 90 (2) ◽  
pp. 470-476 ◽  
Author(s):  
Tian-Zhi Guo ◽  
Frances M. Davies ◽  
Wade S. Kingery ◽  
Andrew J. Patterson ◽  
Lee E. Limbird ◽  
...  
Keyword(s):  
Nitrous Oxide ◽  
Transgenic Mice ◽  
Time Course ◽  
Antinociceptive Effect ◽  
Opiate Receptors ◽  
Opiate Receptor ◽  
Tail Flick ◽  
Wild Type ◽  
Tail Flick Latency ◽  
In The Wild

Background Opiate receptors in the periaqueductal gray region and alpha2 adrenoceptors in the spinal cord of the rat mediate the antinociceptive properties of nitrous oxide (N2O). The availability of genetically altered mice facilitates the detection of the precise protein species involved in the transduction pathway. In this study, the authors establish the similarity between rats and mice in the antinociceptive action of N2O and investigate which alpha2 adrenoceptor subtypes mediate this response. Methods After obtaining institutional approval, antinociceptive dose-response and time-course to N2O was measured in wild-type and transgenic mice (D79N), with a nonfunctional alpha2A adrenoceptor using tail-flick latency. The antinociceptive effect of N2O was tested after pretreatment systemically with yohimbine (nonselective alpha2 antagonist), naloxone (opiate antagonist), L659,066 (peripheral alpha2-antagonist) and prazosin (alpha2B- and alpha2C-selective antagonist). The tail-flick latency to dexmedetomidine (D-med), a nonselective alpha2 agonist, was tested in wild-type and transgenic mice. Results N2O produced antinociception in both D79N transgenic and wild-type litter mates, although the response was less pronounced in the transgenic mice. Antinociception from N2O decreased over time with continuing exposure, and the decrement was more pronounced in the transgenic mice. The antinociceptive response could be dose dependently antagonized by opiate receptor and selective alpha2B-/alpha2C-receptor antagonists but not by a central nervous system-impermeant alpha2 antagonist (L659,066). Whereas dexmedetomidine exhibited no antinociceptive response in the D79N mice, the robust antinociceptive response in the wild-type litter mates could not be blocked by a selective alpha2B-/alpha2C-receptor antagonist. Conclusion These data confirm that the antinociceptive response to an exogenous alpha2-agonist is mediated by an alpha2A adrenoceptor and that there appears to be a role for the alpha2B- or alpha2C-adrenoceptor subtypes, or both, in the analgesic response to N2O.

Antinociceptive Response to Nitrous Oxide Is Mediated by Supraspinal Opiate and Spinal α2Adrenergic Receptors in the Rat

1996 ◽  
Vol 85 (4) ◽  
pp. 846-852 ◽  
Author(s):  
Tian-Zhi Guo ◽  
Lawrence Poree ◽  
Wendy Golden ◽  
Joshua Stein ◽  
Masahiko Fujinaga ◽  
...  
Keyword(s):  
Nitrous Oxide ◽  
Opiate Receptors ◽  
Opioid Analgesics ◽  
Opiate Receptor ◽  
Antagonistic Effect ◽  
Tail Flick ◽  
Endogenous Opiates ◽  
Tail Flick Latency ◽  
Latency Response ◽  
Enclosed Chamber

Background Despite nearly 150 years of clinical use, the mechanism(s) of action of nitrous oxide (N2O) remains in doubt. In some but not all studies the analgesic properties of N2O can be attenuated by opiate receptor antagonists. The purported mechanism for the opiate antagonistic effect relates to the finding that N2O increases supraspinal levels of endogenous opiates, although this finding has been disputed. Based on the observations that (1) N2O promotes the release of catecholamines, including the endogenous alpha 2 adrenergic agonist norepinephrine, and (2) that descending noradrenergic inhibitory pathways are activated by opioid analgesics, this study sought to determine whether alpha 2 adrenergic receptors are involved in the antinociceptive action of nitrous oxide. Methods Institutional approval was obtained for the study. Rats breathed 70% N2O and 30% O2 in an enclosed chamber. After a 30-min exposure, significant antinociception was indicated by an increase in the latency response to a noxious stimulus (tail-flick latency). The tail-flick latency was tested in rats exposed to 70% N2O after either systemic or regional (intrathecal or intracerebroventricular) injections with either competitive (atipamezole; yohimbine) or noncompetitive (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) alpha 2 adrenoceptor antagonists, or the opiate receptor antagonist naloxone. Results When administered systemically, both the opiate (naloxone) and alpha 2 adrenoceptor antagonists (atipamezole, yohimbine, and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) blocked the enhanced tail-flick latency response to N2O-Naloxone administered intracerebroventricularly, but not intrathecally, blocked the enhanced tail-flick latency response to N2O. Conversely, atipamezole administered intrathecally, but not intracerebroventricularly, blocked the enhanced tail-flick latency response to N2O. Conclusions These data suggest that both supraspinal opiate and spinal alpha 2 adrenoceptors play a mediating role in the antinociceptive response to N2O in rats. A possible mechanism may involve a descending inhibitory noradrenergic pathway that may be activated by opiate receptors in the periaqueductal gray region of the brain stem in the rat after exposure to N2O.

Desensitization to the Behavioral Effects of α2-Adrenergic Agonists in Rats

1995 ◽  
Vol 82 (4) ◽  
pp. 954-962. ◽  
Author(s):  
Yukio Hayashi ◽  
Tian-Zhi Guo ◽  
Mervyn Maze
Keyword(s):  
Spinal Cord ◽  
Chronic Treatment ◽  
Behavioral Responses ◽  
Locus Ceruleus ◽  
Tail Flick ◽  
Receptor Density ◽  
Adrenergic Agonists ◽  
Tail Flick Latency ◽  
Latency Response ◽  
Analgesic Response

Background The analgesic and sedative-hypnotic utility of the alpha 2 agonists clonidine and dexmedetomidine are currently being investigated. Both compounds exert their behavioral responses by activating central alpha 2 adrenoceptors, albeit with different selectivities and efficacies. Furthermore, the analgesic and hypnotic behavioral responses are produced at different sites and may be affected independently of one another. A series of studies was conducted in rats to determine (1) whether tolerance and cross-tolerance develop to the analgesic actions of clonidine or dexmedetomidine; (2) how the number of available alpha 2 adrenoceptors affects the analgesic response to dexmedetomidine and clonidine; and (3) how the number of available alpha 2 adrenoceptor affects the hypnotic response to dexmedetomidine. Methods Rats were administered equianalgesic doses of dexmedetomidine or clonidine continuously, subcutaneously by osmotic minipumps. After 7 days the analgesic response to acutely administered dexmedetomidine or clonidine at median effective analgesic doses was assessed by the tail-flick latency response. The number of alpha 2 adrenoceptors in the spinal cord was diminished in a dose-dependent manner by covalent modification with a noncompetitive receptor blocker, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Recovery of the tail-flick latency response to clonidine and dexmedetomidine was determined and correlated to the recovery of receptor density as assessed by radiolabeled-ligand binding studies. The alpha 2 adrenoceptor population in the locus ceruleus of rats was depleted with EEDQ, and recovery of the hypnotic response (as assessed by the loss of righting reflex) to dexmedetomidine was determined and correlated to the recovery of receptor density. Results After 7 days of chronic treatment with dexmedetomidine, analgesic responses to dexmedetomidine and clonidine remained unaltered. However, chronic treatment with clonidine significantly decreased the analgesic effect of clonidine, whereas the analgesic effect to dexmedetomidine was unaffected. In the EEDQ experiments, the analgesic response to dexmedetomidine was restored to normal when 44% of the alpha 2 adrenoceptors in the spinal cord were available for agonist binding; comparatively more alpha 2 adrenoceptors (77%) were required for the analgesic response to clonidine to be restored. The recovery of the hypnotic response to dexmedetomidine after EEDQ treatment was retarded when compared with the recovery of the analgesic response to that compound. Greater than 77% of alpha 2 adrenoceptors in the locus ceruleus must be available for the hypnotic response to alpha 2 agonists to be expressed. Conclusions Fewer alpha 2 adrenoceptors need to be available for analgesia to be produced by dexmedetomidine compared with the number required for analgesia by clonidine. This difference should result in less tolerance in the analgesic response to dexmedetomidine than to clonidine with chronic use. Dexmedetomidine requires fewer alpha 2 adrenoceptors to elicit an analgesic response than it does to elicit a hypnotic response. Thus the analgesic properties of alpha 2-adrenergic agonists persist after the hypnotic response has been attenuated after chronic alpha 2 agonist administration.

Functional organization of trigeminal subnucleus interpolaris: nociceptive and innocuous afferent inputs, projections to thalamus, cerebellum, and spinal cord, and descending modulation from periaqueductal gray

1984 ◽  
Vol 51 (5) ◽  
pp. 890-905 ◽  
Author(s):  
H. Hayashi ◽  
R. Sumino ◽  
B. J. Sessle
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Dynamic Range ◽  
Functional Organization ◽  
Periaqueductal Gray ◽  
Spinal Cord Dorsal Horn ◽  
Tooth Pulp ◽  
Antidromic Activation ◽  
Nociceptive Neurons ◽  
Afferent Inputs

In view of continuing uncertainties concerning the organization, afferent inputs, and projection sites of neurons in the subnucleus interpolaris of the trigeminal (V) spinal tract nucleus, the characteristics of 222 single neurons in and adjacent to the subnucleus were examined electrophysiologically in adult cats anesthetized with chloralose. Neurons were tested for orthodromic responsiveness to a variety of stimuli that included nonnoxious tactile stimuli, noxious mechanical and radiant-heat stimuli, and graded electrical stimulation of the skin, mucosa, tooth pulp, and masseter nerve. Antidromic activation techniques were also used to determine if the functionally identified neurons projected directly to the contralateral posterior thalamus, ipsilateral cerebellum, or cervical spinal cord. In addition, the periaqueductal gray matter (PAG) was stimulated to test for conditioning influences from the PAG on orthodromic responses to noxious and nonnoxious oral-facial stimuli. Interpolaris neurons were somatotopically arranged in subnucleus interpolaris in a pattern conforming in general to the medially facing, inverted-head representation characteristic of other parts of the V brain stem sensory nuclear complex. On the basis of their responsiveness to cutaneous stimuli, the neurons could be functionally classified as either cutaneous nociceptive or low-threshold mechanoreceptive (LTM) neurons. The LTM neurons constituted the major neuron type, accounting for over 75% of our neuron sample. Most of them had a localized mechanoreceptive field of less than 100 mm2 in area that was restricted to one V division, and they had skin-evoked response latencies indicative of afferent input predominantly from A-beta cutaneous afferents. A population of nociceptive neurons was also encountered in the lateral, marginal region of interpolaris and at its medial or ventral border with the reticular formation. These neurons were of two types: nociceptive-specific (NS) neurons, which did not respond to nonnoxious stimuli but which required noxious stimuli for their activation; and wide dynamic range ( WDR ) neurons, which responded to both noxious and nonnoxious stimuli applied to the facial skin. Most had an ipsilateral receptive field that was greater than 100 mm2 in area and that often involved two or three V divisions. Their properties generally conformed to those previously described for nociceptive neurons in the medullary dorsal horn (V subnucleus caudalis) and spinal cord dorsal horn. Interpolaris neurons of all classes (LTM, WDR , and NS) were found to have direct axonal projections to the thalamus, cerebellum, and spinal cord.(ABSTRACT TRUNCATED AT 400 WORDS)

Opiate receptors in the periaqueductal gray mediate analgesic effect of nitrous oxide in rats

1997 ◽  
Vol 336 (2-3) ◽  
pp. 137-141 ◽  
Author(s):  
Fang Fang ◽  
Tian-Zhi Guo ◽  
M.Frances Davies ◽  
Mervyn Maze
Keyword(s):  
Nitrous Oxide ◽  
Analgesic Effect ◽  
Opiate Receptors ◽  
Periaqueductal Gray
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