"Exciting" aspects of opiate receptor signal transduction.
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Animals↗
Biomedical subjects
M Maze
Publications and source records attributed to M Maze.
Why does insensitivity to opioid narcotics develop?
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Humans↗
Nifedipine, an L-type calcium channel blocker, restores the hypnotic response in rats made tolerant to the alpha-2 adrenergic agonist dexmedetomidine.
Rats were made tolerant to the hypnotic effects of the alpha-2 adrenergic agonist dexmedetomidine by a 7- or 14-day continuous systemic administration of the same, and the ability of nifedipine to reverse dexmedetomidine tolerance was assessed. Acute administration of nifedipine (10 mg/kg i.p.) restored the hypnotic response to dexmedetomidine in the alpha-2 tolerant rats. Concurrent administration of nifedipine during induction of tolerance, either partially (continuous administration 10 mg/kg/day delivered by minipumps) or completely (twice daily injections, 20 mg/kg s.c.) restored hypnotic responsiveness to control levels. Induction of tolerance reduced the affinity of [3H]PN200-110 for the L-type calcium channel. Chronically administered nifedipine treatment (20 mg/kg s.c. twice daily), at doses that partially restored the behavioral response to normal, did not change ligand binding affinity of [3H]PN200-110. An increase in Bmax for [3H]PN200-110 was noted in the dexmedetomidine tolerant state which did not change with chronic nifedipine. In naive rats, the phosphodiesterase inhibitor rolipram (275 microg/kg i.p.), mimicked the state of tolerance, as it resulted in a decreased hypnotic response to dexmedetomidine. Nifedipine (10 mg/kg i.p.) also reversed the rolipram-induced attenuation of the hypnotic response to dexmedetomidine. These data implicate a role for the L-type calcium channel in the mechanism of the hypnotic response in alpha-2 tolerant rats and suggest the involvement of the cAMP pathway.
Adrenergic alpha-2 Receptor Agonists↗
Antisense technology reveals the alpha2A adrenoceptor to be the subtype mediating the hypnotic response to the highly selective agonist, dexmedetomidine, in the locus coeruleus of the rat.
Alpha2 adrenergic agonists are used in the anesthetic management of the surgical patient for their sedative/hypnotic properties although the alpha2 adrenoceptor subtype responsible for these anesthetic effects is not known. Using a gene-targeting strategy, it is possible to specifically reduce the expression of the individual adrenoceptors expressed in the central nervous system and to thereby determine their role in hypnotic action. Stably transfected cell lines (PC 124D for rat alpha2A; NIH3T3 for rat alpha2C adrenoceptors) were exposed to 5 microM antisense oligodeoxynucleotides (ODNs) for alpha2A and alpha2C adrenergic receptor subtypes for 3 d. Individual receptor subtype expression, as determined by radiolabeled ligand binding, was selectively decreased only by the appropriate antisense ODNs and not by the "scrambled" ODNs. These antisense ODNs were then administered three times, on alternate days, into the locus coeruleus of chronically cannulated rats and their hypnotic response to dexmedetomidine (an alpha2 agonist) was determined. Only the alpha2A antisense ODNs significantly change the hypnotic response causing both an increase in latency to, and a decrease in duration of, the loss of righting reflex following dexmedetomidine; hypnotic response had normalized 8 d after stopping the ODNs. Therefore, the alpha2A adrenoceptor subtype is responsible for the hypnotic response to dexmedetomidine in the locus coeruleus of the rat.
Adrenergic alpha-Agonists↗
Role of serotonergic neurotransmission in the hypnotic response to dexmedetomidine, an alpha 2-adrenoceptor agonist.
The role of serotonergic pathways in the hypnotic response to dexmedetomidine was examined in neurochemical and behavioral studies. Following acute administration of dexmedetomidine, loss of righting reflex and changes in serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine turnover in different brain regions (locus coeruleus and hippocampus) were assessed. In separate experiments, the effect of dexmedetomidine on 5-HT turnover was measured in rats rendered tolerant to the hypnotic effects of dexmedetomidine. These neurochemical data were complemented by a study of dexmedetomidine-induced hypnotic response in the presence of a 5-HT2 receptor agonist and antagonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and ritanserin, respectively. Dexmedetomidine (1-500 micrograms.kg-1) dose dependently reduced 5-HT and norepinephrine turnover in both the locus coeruleus and hippocampus. The decrease in 5-HT turnover more closely correlated with the dose-response curve for loss of righting reflex, a behavioral measure of hypnosis, than did the norepinephrine turnover. In previous studies with chronic administration of dexmedetomidine (3 micrograms.kg-1.h-1 for 7 days), the norepinephrine turnover effect of acute dexmedetomidine (30 micrograms.kg-1) persisted while the hypnotic effect was blunted. Following the same regimen, the drug's ability to diminish 5-HT turnover was also blunted. This biochemical evidence for the role of 5-HT in sleep was supported by the behavioral evidence that dexmedetomidine (100 micrograms.kg-1 i.p. or 7 micrograms.0.2 microliter-1 locus coeruleus)-induced hypnosis was dose dependently blocked by DOI (0.08-0.32 mg.kg-1 i.p.). The selectivity of this effect was demonstrated by the finding that ritanserin (0.16 mg.kg-1 i.p.) pretreatment blocked the effects of DOI (0.16 mg.kg-1 i.p.) on dexmedetomidine (100 micrograms.kg-1 i.p. or 7 micrograms.0.2 microliter-1 locus coeruleus)-induced loss of righting reflex. In conclusion, these findings suggest that the hypnotic effect of the alpha 2-adrenoceptor agonist, dexmedetomidine, is not mediated solely by changes in noradrenergic neurtransmission, but instead is strongly associated with a decrease in serotonergic neurotransmission and correspondingly diminished by stimulation of 5-HT2 receptors.
Adrenergic alpha-Agonists↗
Arrangement of transmembrane domains in adrenergic receptors. Similarity to bacteriorhodopsin.
G protein-coupled receptors (GPCRs) have seven hydrophobic domains, which are thought to span the lipid bilayer as alpha helical transmembrane domains (TMDs). The tertiary structure of GPCRs has not been determined; however, molecular models of GPCRs have generally been based on bacteriorhodopsin, which is functionally unrelated to GPCRs but has a similar secondary structure. We sought to examine the validity of using bacteriorhodopsin as a scaffold for GPCR model building by experimentally determining the orientation of the TMDs of adrenergic receptors in the plasma membrane. In separate experiments, three sequential amino acid residues (Leu-310, Leu-311, Asn-312) in TMD VII of the beta 2 adrenoreceptors were mutated to the amino acids found in the homologous domain of the alpha 2 adrenoceptor (Phe, Phe, Phe). Exchange of Asn-312 and Leu-311 in the beta 2 adrenoceptor resulted in nonfunctional proteins, most likely due to incompatibility of the introduced bulky phenylalanine side chain with adjacent structural domains in the beta 2 adrenoreceptor. This structural incompatibility was "repaired" by replacing the specific beta 2 TMD sequence with an alpha 2 receptor sequence. TMD I and TMD II complemented the Asn-312-->Phe mutation, and TMD III and TMD VI complemented the Leu-311-->Phe mutation. These results indicate that TMDs I, II, III, and VI surround TMD VII in a counter-clockwise orientation analogous to the orientation of TMDs in bacteriorhodopsin.
Animals↗
Hypnotic and analgesic effects of the alpha 2-adrenergic agonist dexmedetomidine in morphine-tolerant rats.
Combinations of alpha 2 agonists and opiates are used in the clinical management of pain to harness their potential synergistic interaction for analgesia while limiting their side-effects. To better predict the clinical consequences of this combination, we studied the behavioral effects of dexmedetomidine, a highly selective alpha 2 agonist with analgesic and hypnotic properties, during the development of, and recovery from, morphine tolerance. Rats were implanted with morphine pellets (or placebo), daily for 5 days. The analgesic response to morphine, dexmedetomidine, or the combination of the two drugs was assessed with the tail-flick latency response. The hypnotic response to dexmedetomidine, and to the combination of dexmedetomidine and morphine, was measured by the duration of the loss of righting reflex (sleep-time). One day after the last morphine pellet implantation, alpha 2 adrenoceptor binding was assessed in vitro in the locus coeruleus (LC) and the spinal cord (SC). Data were analyzed by analysis of variance (ANOVA), t-test, or Mann-Whitney test. The morphine tolerance was present after 1 day of morphine administration. At Days 1 and 3 of morphine administration, the hypnotic and analgesic responses to dexmedetomidine were significantly increased. After 5 days of morphine treatment, the analgesic response to dexmedetomidine was unaltered, while the hypnotic response to dexmedetomidine was now significantly decreased. The kd for the alpha 2 adrenoceptors was unaffected while the Bmax was significantly decreased only in the SC. Acutely administered morphine significantly enhanced the hypnotic and analgesic effects of dexmedetomidine in naive rats but not in morphine-tolerant rats. During morphine withdrawal, the hypnotic response to dexmedetomidine normalized; however, the analgesic response to dexmedetomidine was significantly decreased 5 days after withdrawal before returning to normal at Day 10 after withdrawal. We conclude that in the development of, and recovery from, the morphine-tolerant state, the hypnotic and analgesic responses to alpha 2 agonists are asynchronous.
Adrenergic alpha-Agonists↗
Dexmedetomidine injection into the locus ceruleus produces antinociception.
BACKGROUND: Alpha(2)-Adrenergic agonists such as clonidine and dexmedetomidine are known to produce sedation and analgesia in humans. The sedative effect of these agents is thought to occur through supraspinal pathways, involving the locus ceruleus (LC) and its projections in rats. While the antinociceptive response to alpha(2) agonists, given intrathecally, is mediated predominantly in the spinal cord, other sites of action have not been systematically studied. The authors examined whether alpha(2)-adrenergic receptors in the LC mediate an antinociceptive effect. METHODS: For administration of different drugs into the LC, guide cannulas were placed with their tips in the LC in male Sprague-Dawley rats. Dexmedetomidine (3.5 micrograms/0.2 microliter) was microinjected into the LC through the cannula, or given systemically by intraperitoneal injecton (50 micrograms/kg). The antinociceptive effect of dexmedetomidine was measured using the tail-flick latency response. To determine the sites through which dexmedetomidine injection into the LC produces antinociception, the authors examined whether this response could be perturbed by the specific alpha(2)-adrenergic antagonists atipamezole and L659,066 and pertussis toxin administered either into the LC or intrathecally before injection of dexmedetomidine systemically or directly into the LC. To eliminate the possibility that drug administered in one site (LC or intrathecal) could reach the other site, the dispositional characteristics of radiolabeled dexmedetomidine (LC) or atipamezole (intrathecal) were studied. RESULTS: Dexmedetomidine placed into the LC produces a dose-dependent increase in the tail-flick latency. This antinociceptive effect was blocked by pertussis toxin and by the alpha(2) antagonists atipamezole and L659,066 placed in the LC. Intrathecal administration of atipamezole and pertussis toxin also blocked the antinociceptive effect of dexmedetomidine placed in the LC. (3)H-dexmedetomidine introduced into the LC did not reach the spinal cord in pharmacologically active concentrations; also, intrathecally administered (3)H-atipamezole did not reach the LC in appreciable amounts. The systemic administration of dexmedetomidine produced an increase in tail-flick latency, and this effect was attenuated by the injection of atipamezole and L659,066 into the LC. CONCLUSIONS: Part of the mechanism by which dexmedetomidine produces an antinociceptive effect is by an action directly on the LC, demonstrated by these studies in which antinociception produced by injection of this drug into the LC can be blocked by specific alpha(2) antagonists injected into the LC. Furthermore, the action of dexmedetomidine in the LC in turn may result in an increase in activation of alpha(2) adrenoceptors in the spinal cord, because the antinociceptive effect of LC dexmedetomidine injection also can be blocked by intrathecal injection of antipamezole and pertussis toxin.
Adrenergic alpha-2 Receptor Agonists↗
Sympatholytic and minimum anesthetic concentration-sparing responses are preserved in rats rendered tolerant to the hypnotic and analgesic action of dexmedetomidine, a selective alpha(2)-adrenergic agonist.
BACKGROUND: The development of tolerance to the sympatholytic and anesthetic-reducing effects of alpha(2) agonists after prolonged administration of dexmedetomidine and how the number of available alpha(2) adrenoceptors affects these dexmedetomidine-induced responses was studied. METHODS: The sympatholytic action of acute and chronic (3 and 10 micrograms.kg-1.h-1 for 7 days) dexmedetomidine, was assessed by the decrease in norepinephrine turnover in the locus coeruleus and hippocampus. The anesthetic-reducing effect of chronic (7 days) dexmedetomidine (5 and 10 micrograms.kg-1.h-1) was studied by determining the minimum alveolar concentration (MAC) for halothane that prevented rats from responding to a supramaximal noxious stimulus of dexmedetomidine (10 or 30 micrograms.kg-1), doses in the steep part of the dose-response curve. The receptor reserve for the norepinephrine turnover and anesthetic-sparing responses to dexmedetomidine was delineated with 0.3-1.0 mg.kg-1 N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, an irreversible alkylating agent. RESULTS: After chronic administration of dexmedetomidine at both doses, acute dexmedetomidine significantly decreased norepinephrine turnover in the hippocampus and locus coeruleus. The baseline minimum anesthetic concentration (MAC) and the MAC-sparing effect to acutely administered dexmedetomidine were preserved after chronic dexmedetomidine treatment. In the N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline experiments, the dexmedetomidine-induced norepinephrine turnover effect required less than 20% and greater than 4% alpha(2) adrenoceptor availability in the locus coeruleus and the dexmedetomidine induced MAC-sparing effect required less than 40% and greater than 20% alpha(2) adrenoceptor availability in the locus coeruleus. CONCLUSION: Tolerance does not develop for either the sympatholytic or MAC-sparing actions of dexmedetomidine, although it is present for the hypnotic response. The durable quality of the sympatholytic and MAC-sparing responses to dexmedetomidine after chronic treatment is explained by a comparatively larger receptor reserve than is needed for the hypnotic and analgesic responses, which are blunted by the same drug treatment regimen.
Adrenergic alpha-2 Receptor Agonists↗
Antinociceptive response to nitrous oxide is mediated by supraspinal opiate and spinal alpha 2 adrenergic receptors in the rat.
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.
Adrenergic alpha-Antagonists↗
Dexmedetomidine does not attenuate increases in excitatory amino acids after transient global ischemia in the rabbit.
This study was designed to evaluate the ability of dexmedetomidine, an alpha 2-adrenergic agonist, to attenuate increases in the hippocampal concentration of extracellular glutamate and glycine that result from episodes of transient global cerebral ischemia. After the induction of anesthesia with halothane and oxygen, microdialysis catheters were stereotactically inserted into the hippocampi of 16 New Zealand white rabbits. After the collection of baseline samples of dialysate, animals were randomly assigned to receive an intravenous infusion of either saline (n = 8) or dexmedetomidine (n = 8). Transient global cerebral ischemia was produced by the inflation of a neck tourniquet and induction of deliberate hypotension for 10 min. Dialysates were collected during the ischemic period and for the ensuing 60 min of reperfusion. During ischemia, the concentrations of glutamate and glycine increased from the preischemic baseline in both groups. Glutamate concentrations rapidly returned to baseline after reperfusion, whereas glycine concentrations remained elevated throughout the reperfusion period. There were no significant differences between the control and dexmedetomidine-treated groups. These results suggest that the mechanism of the putative neuroprotective effects of dexmedetomidine is not related to decreased concentrations of glutamate or glycine.
Adrenergic alpha-Agonists↗
Desensitization to the behavioral effects of alpha 2-adrenergic agonists in rats.
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.
Adrenergic alpha-Agonists↗
Role of pertussis toxin-sensitive G-proteins in the analgesic and anesthetic actions of alpha 2-adrenergic agonists in the rat.
BACKGROUND: alpha 2 Adrenoceptors are coupled to G-proteins sensitive to pertussis toxin (PTX) in the locus coeruleus. At this site, the hypnotic response to dexmedetomidine, an alpha 2 agonist, can be blocked by pretreatment with PTX. G-proteins sensitive to PTX may also be involved in the transduction of anesthetic and analgesic responses to alpha 2 agonists at supraspinal or spinal sites. To address this question the effects of pretreatment with PTX administered intracerebroventricularly, intrathecally, or a combination of the two were examined on the MAC for halothane, and the anesthetic-sparing and analgesic effects of a systemically administered alpha 2 agonist, dexmedetomidine. METHODS: Rats were cannulated intracerebroventricularly, intrathecally, and with a combination of intracerebroventricular/intrathecal and treated with PTX (0 and 2.5 micrograms intracerebroventricularly; 0 or 0.5 microgram intrathecally; 0 + 0 or 2.5 + 0.5 intracerebroventricular-intrathecal)). After 7 days, either the analgesic (tail-flick latency) or the MAC-sparing effects of a calculated 50% effective dose of dexmedetomidine were measured. To confirm that intracerebroventricularly administered PTX was effective, ribosylation of G-proteins was assessed in periventricular brain tissue. RESULTS: The analgesic action of dexmedetomidine was blocked by PTX intrathecally but not by PTX via the intracerebroventricular route. The MAC-sparing action of dexmedetomidine was not blocked by PTX via the intrathecal or intracerebroventricular routes alone or in combination. Yet, intracerebroventricularly administered PTX effectively ribosylated the G-proteins. CONCLUSIONS: Taken together with the authors' previous report, these data suggest that the hypnotic and the analgesic responses to dexmedetomidine are transduced via PTX-sensitive G-protein-coupled alpha 2 adrenoceptors but at separate sites (analgesic-spinal; hypnotic-locus coeruleus). Further studies are needed to localize the precise site(s) for the MAC-sparing effect of dexmedetomidine and to establish whether PTX-sensitive G-proteins are involved in this response.
Adrenergic alpha-2 Receptor Agonists↗
Alpha 2-adrenoceptor agonists and anesthesia.
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Adrenergic alpha-Agonists↗
Alpha-2 adrenergic modulation of sleep: time-of-day-dependent pharmacodynamic profiles of dexmedetomidine and clonidine in the rat.
Alpha adrenergic agonists such as clonidine are widely used for their antihypertensor effects, but they also cause sedation. The mechanisms underlying soporific effects of such compounds are poorly understood, but appear to involve the alpha-2 adrenergic receptor sub-type. To further investigate the role of this receptor in sleep-wake regulation, rats received injections i.p. either during their peak of activity (circadian time CT-18: 6 hr after lights out) or near the mid-point of their sleep-dominated phase (CT-5: 5 hr after lights on) with either the highly selective alpha-2 agonist dexmedetomidine (dMED) 0.02 to 0.04 mg/kg or the less selective alpha-2 agonist, clonidine 0.04 to 0.08 mg/kg, or vehicle. Clonidine and dMED showed remarkable overall similarities in their soporific profiles. Except for the lower dose of clonidine, both CT-5 and CT-18 treatments increased the percent of time spent in non-REM (NREM) sleep. The increase in NREM was followed by a reduction of NREM sleep that was accompanied by locomotor activity and body temperature above control levels. After CT-5 treatments, this period of reduced NREM sleep was followed by a secondary increase in NREM 7 to 10 hr posttreatment. REM sleep was markedly reduced for 9 to 10 hr after all treatments at both times of day, with elevated REM levels 18 to 30 hr posttreatment. Pre-treatment with the selective alpha-2 antagonist atipamezole (0.5 mg/kg) reversed the effects of CT-18 dMED 0.04 mg/kg except REM sleep suppression, which was only partially reversed. The NREM-inducing potency of dMED 0.02 mg/kg was greater when administered at CT-18 than at CT-5. Taken together with other evidence, these findings suggest that the profound NREM-inducing effects of dMED may be mediated by postsynaptic alpha-2 adrenoceptors. Furthermore, the pharmacodynamic action of alpha-2 adrenergic agonists, like many other sedative hypnotics (e.g., benzodiazepines), produce a hysteresis in sleep-wake regulation characterized by "rebound" waking after drug-induced sleep.
Adrenergic alpha-Agonists↗
Chronic administration of an alpha 2 adrenergic agonist desensitizes rats to the anesthetic effects of dexmedetomidine.
alpha 2 adrenergic agonists are being administered perioperatively to facilitate the anesthetic management of the surgical patient. In some clinical settings, use of alpha 2 adrenergic agonists has been extended into the postoperative period to prolong the patients' sedative and stress-free state. We studied whether the administration of alpha 2 adrenergic agonists over an extended period of time would result in "desensitization" to the central actions of alpha 2 adrenergic agonists. Male Sprague-Dawley rats were administered dexmedetomidine, a highly selective alpha 2 adrenergic agonist, at rates varying between 1 and 10 micrograms.kg-1.h-1 via a chronically implanted SC osmotic pump. Spontaneous locomotor activity, tested in an open-field box, was significantly lower in both 3- and 10-micrograms.kg-1.h-1 treatment groups but returned to normal by the second or sixth day, respectively. The hypnotic response to dexmedetomidine IP was decreased in the 10-micrograms.kg-1.h-1 dose group from the second day, and by the fourth day in the 3-micrograms.kg-1.h-1 group. Recovery from the desensitized state was rapid and occurred on the third day after pump removal in the 3-micrograms.kg-1.h-1 group and by the fifth day after pump removal in the 10-micrograms.kg-1.h-1 dose group. By using a higher dose of dexmedetomidine IP (250 micrograms.kg in lieu of 100 micrograms/kg) at day 7 in "tolerant" rats, the hypnotic response could partially be "restored" towards normal. An attenuated hypnotic response could still be demonstrated even when dexmedetomidine was administered directly into the locus coeruleus (LC) in rats pretreated chronically with dexmedetomidine.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic alpha-Agonists↗
Perturbation of ion channel conductance alters the hypnotic response to the alpha 2-adrenergic agonist dexmedetomidine in the locus coeruleus of the rat.
BACKGROUND: The alpha 2-adrenergic agonists are members of a novel class of hypnotic-anesthetic agents that selectively bind to alpha 2 adrenoceptors in the locus coeruleus (LC) to initiate their pharmacologic action. The postreceptor molecular mechanism of the hypnotic action of alpha 2-adrenergic agonists remains unknown. In this study we addressed the role of conductance through a variety of calcium and potassium ion channels in the hypnotic action of dexmedetomidine in the LC of the rat. METHODS: Cannulas were inserted stereotactically into the LC of halothane-anesthetized rats (n = 318). After at least 48 h, rats were tested for loss of righting reflex in response to administration of the alpha 2-adrenergic agonist dexmedetomidine at a hypnotic (7.0 micrograms LC) or subhypnotic (3.5 micrograms LC) dose. To establish the mediating role of various species of calcium and potassium ion channels in the hypnotic response, rats were pretreated with the following drugs before the administration of dexmedetomidine LC:S(+)202791 (L-type calcium-channel activator), nifedipine and R(-)202791 (L-type calcium-channel blocker), SNX 111 (N-type calcium-channel blocker), SNX 230 (P-type calcium-channel blocker), quinine (calcium-activated and voltage-gated potassium-channel blocker), charybdotoxin (calcium-activated potassium-channel blocker), dendrotoxin (voltage-gated potassium-channel blocker), or glybenclamide (adenosine triphosphate-sensitive potassium-channel blocker). The drugs were used in doses not causing behavioral effects that could have confounded the interpretation of loss of righting reflex. RESULTS: SNX 230 and the dihydropyridines nifedipine and R(-)202791 produced loss of righting reflex in the presence of a subhypnotic dose of dexmedetomidine. The hypnotic-enhancing effects of the dihydropyridines could be blocked with S(+)202791, which also diminished loss of righting reflex in response to dexmedetomidine 7.0 micrograms LC. Quinine, dendrotoxin, and charybdotoxin each attenuated the hypnotic response to dexmedetomidine 7.0 micrograms LC. The hypnotic response to dexmedetomidine was not significantly altered by SNX 111 or glybenclamide. CONCLUSIONS: Inhibition of ion conductance through L- or P-type calcium channels and facilitation of conductance through voltage-gated or calcium-activated potassium channels may be involved in the mechanism of hypnotic action of alpha 2-adrenergic agonists. These changes in ion conductance were capable of producing membrane hyperpolarization and decreasing neuronal excitability. There was no evidence for the involvement of adenosine triphosphate-sensitive potassium channels or N-type calcium channels in the hypnotic response to dexmedetomidine.
Adrenergic alpha-Agonists↗
The alpha 2 adrenergic agonist, dexmedetomidine, selectively attenuates ischemia-induced increases in striatal norepinephrine concentrations.
This study was designed to evaluate the ability of a selective alpha 2 adrenergic agonist (dexmedetomidine) to attenuate ischemia-induced increases in striatal norepinephrine, 3 methoxy-4-hydroxyphenethyleneglycol (MHPG), dopamine, and 5-hydroxyindoleacetic acid (5-HIAA). Following the induction of anesthesia with halothane and oxygen, microdialysis catheters were stereotactically inserted into the striatum of 9 New Zealand white rabbits. Monitored variables included epidural temperature, arterial blood gases and pH, mean arterial pressure, blood glucose concentrations and the electroencephalogram. Following collection of baseline samples of dialysate, animals were randomized to receive a continuous infusion of saline (n = 4) or dexmedetomidine (n = 5). Cerebral ischemia was produced by the inflation of a neck tourniquet and induction of deliberate hypotension. Dialysate collection continued during the ischemic period and for the ensuing 140 min of reperfusion. All dialysate was frozen at -80 degrees C prior to its analysis by liquid chromatography for catecholamine content. There were no significant differences between the two groups for temperature, arterial blood gases, or mean arterial pressure. Blood glucose concentrations increased in the dexmedetomidine group. The electroencephalogram became isoelectric within 30 s of tourniquet inflation in all animals. Analysis of the norepinephrine and MHPG levels revealed significantly lower values for the dexmedetomidine-treated group during and following the ischemic period. There were no differences between groups for extracellular dopamine or 5-HIAA concentrations. These results suggest that the alpha 2 agonist dexmedetomidine can selectively attenuate ischemia-induced increases in striatal norepinephrine concentrations.
Adrenergic alpha-Agonists↗