Corticotropin-releasing Factor Mediates the Antinociceptive Action of Nitrous Oxide in Rats

2003 ◽  
Vol 99 (3) ◽  
pp. 708-715 ◽  
Author(s):  
Shigehito Sawamura ◽  
Mizuki Obara ◽  
Kenji Takeda ◽  
Mervyn Maze ◽  
Kazuo Hanaoka
Keyword(s):  
Nitrous Oxide ◽  
Antinociceptive Effect ◽  
Locus Ceruleus ◽  
Corticotropin Releasing Factor ◽  
Tail Flick ◽  
Intracerebroventricular Administration ◽  
Noradrenergic Neurons ◽  
Sprague Dawley ◽  
Antinociceptive Action ◽  
Fos Expression

Background Exposure to nitrous oxide activates brainstem noradrenergic nuclei and descending inhibitory pathways, which produce the acute antinociceptive action of nitrous oxide. Because corticotropin-releasing factor (CRF) can produce activation of noradrenergic neurons in the locus ceruleus, the authors sought to determine whether it might be responsible for the antinociceptive action of nitrous oxide. Methods Male Sprague-Dawley rats (250-300 g) were exposed for 60 min to room air or 25, 50 or 70% nitrous oxide in oxygen. Brain sections including the hypothalamus were immunostained for both c-Fos (a marker of neuronal activation) and CRF and the percentage of CRF-positive neurons expressing c-Fos was determined. The functional consequences of changes in CRF were investigated by assessing the effect of intracerebroventricular administration of a CRF antagonist (alpha-helical CRF9-41, 20 microg/10 microl) on both activation of locus ceruleus noradrenergic neurons and the antinociception (with the tail-flick latency test) produced by nitrous oxide. Results Inhalation of nitrous oxide induced a dose-dependent increase in c-Fos expression in CRF-positive neurons in the paraventricular nucleus of the hypothalamus. Intracerebroventricular administration of CRF antagonist inhibited nitrous oxide-induced c-Fos expression in the locus ceruleus and the antinociceptive effect of nitrous oxide. Conclusions Nitrous oxide activates the CRF system in the brain, which results in stimulation of noradrenergic neurons in the locus ceruleus and its consequent antinociceptive effect.

Dexmedetomidine Injection into the Locus Ceruleus Produces Antinociception

1996 ◽  
Vol 84 (4) ◽  
pp. 873-881. ◽  
Author(s):  
Tian-Zhi Guo ◽  
Jian-Yu Jiang ◽  
Ann E. Buttermann ◽  
Mervyn Maze
Keyword(s):  
Spinal Cord ◽  
Pertussis Toxin ◽  
Antinociceptive Effect ◽  
Intrathecal Injection ◽  
Locus Ceruleus ◽  
Tail Flick ◽  
Sprague Dawley ◽  
Tail Flick Latency ◽  
Pharmacologically Active ◽  
Sites Of Action

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.

scholarly journals Effects of peripheral FAAH blockade on NTG-induced hyperalgesia—evaluation of URB937 in an animal model of migraine

Cephalalgia ◽  
2015 ◽  
Vol 35 (12) ◽  
pp. 1065-1076 ◽  
Author(s):  
R Greco ◽  
T Bandiera ◽  
AS Mangione ◽  
C Demartini ◽  
F Siani ◽  
...  
Keyword(s):  
Animal Model ◽  
Antinociceptive Effect ◽  
Acid Amide ◽  
Male Rats ◽  
Tail Flick ◽  
Tail Flick Test ◽  
Brain Nuclei ◽  
Nociceptive Responses ◽  
Fos Expression ◽  
Baseline Conditions

Background Systemic nitroglycerin (NTG) activates brain nuclei involved in nociceptive transmission as well as in neuroendocrine and autonomic functions in rats. These changes are considered relevant for migraine because NTG consistently provokes spontaneous-like migraine attacks in migraineurs. Several studies have suggested a relationship between the endocannabinoid levels and pain mediation in migraine. URB937, a peripheral inhibitor of fatty acid amide hydrolase (FAAH)—the enzyme that degrades anandamide, produces analgesia in animal models of pain, but there is no information on its effects in migraine. Aim We evaluated whether URB937 alters nociceptive responses in the animal model of migraine based on NTG administration in male rats, using the tail flick test and the plantar and orofacial formalin tests, under baseline conditions and after NTG administration. Furthermore, we investigated whether URB937 affects NTG-induced c-Fos expression in the brain. Results During the tail flick test, URB937 showed an antinociceptive effect in baseline conditions and it blocked NTG-induced hyperalgesia. URB937 also proved effective in counteracting NTG-induced hyperalgesia during both the plantar and orofacial formalin tests. Mapping of brain nuclei activated by NTG indicates that URB937 significantly reduces c-Fos expression in the nucleus trigeminalis caudalis and the locus coeruleus. Conclusions The data suggest that URB937 is capable of changing, probably via indirect mechanisms, the functional status of central structures that are important for pain transmission in an animal model of migraine.

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).

Nitrous Oxide Lacks the Antinociceptive Effect on the Tail Flick Test in Newborn Rats

2000 ◽  
Vol 91 (1) ◽  
pp. 6-10 ◽  
Author(s):  
Masahiko Fujinaga ◽  
Ryan Doone ◽  
M. Frances Davies ◽  
Mervyn Maze
Keyword(s):  
Nitrous Oxide ◽  
Antinociceptive Effect ◽  
Tail Flick ◽  
Newborn Rats ◽  
Tail Flick Test

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.

scholarly journals Modulation of Morphine-induced Antinociception in Acute and Chronic Opioid Treatment by Ibudilast

2009 ◽  
Vol 111 (6) ◽  
pp. 1356-1364 ◽  
Author(s):  
Tuomas O. Lilius ◽  
Pekka V. Rauhala ◽  
Oleg Kambur ◽  
Eija A. Kalso
Keyword(s):  
Cell Activation ◽  
Antinociceptive Effect ◽  
Opioid Analgesics ◽  
Morphine Tolerance ◽  
Tail Flick ◽  
Sprague Dawley ◽  
Tail Flick Test ◽  
Glial Cell Activation ◽  
Sprague Dawley Rats ◽  
Antinociceptive Effects

Background Opioid analgesics are effective in relieving chronic pain, but they have serious adverse effects, including development of tolerance and dependence. Ibudilast, an inhibitor of glial activation and cyclic nucleotide phosphodiesterases, has shown potential in the treatment of neuropathic pain and opioid withdrawal. Because glial cell activation could also be involved in the development of opioid tolerance in rats, the authors studied the antinociceptive effects of ibudilast and morphine in different models of coadministration. Methods Antinociception was assessed using male Sprague- Dawley rats in hot plate and tail-flick tests. The effects of ibudilast on acute morphine-induced antinociception, induction of morphine tolerance, and established morphine tolerance were studied. Results Systemic ibudilast produced modest dose-related antinociception and decreased locomotor activity at the studied doses of 2.5-22.5 mg/kg. The highest tested dose of 22.5 mg/kg produced 52% of the maximum possible effect in the tail-flick test. It had an additive antinociceptive effect when combined with systemic morphine. Coadministration of ibudilast with morphine did not attenuate the development of morphine tolerance. However, in morphine-tolerant rats, ibudilast partly restored morphine-induced antinociception. Conclusions Ibudilast produces modest antinociception, and it is effective in restoring but not in preventing morphine tolerance. The mechanisms of the effects of ibudilast should be better understood before it is considered for clinical use.

scholarly journals Spinal Antinociceptive Action of Amiloride and Its Interaction with Tizanidine in the Rat Formalin Test

2015 ◽  
Vol 20 (6) ◽  
pp. 321-326 ◽  
Author(s):  
Handong Ouyang ◽  
Peizong Wang ◽  
Wan Huang ◽  
Qiang Li ◽  
Bilin Nie ◽  
...  
Keyword(s):  
Side Effects ◽  
Adrenergic Receptor ◽  
Formalin Test ◽  
Antinociceptive Effect ◽  
Formalin Injection ◽  
Nociceptive Response ◽  
Sprague Dawley ◽  
Allosteric Site ◽  
Isobolographic Analysis ◽  
Antinociceptive Action

BACKGROUND: Amiloride has been reported to produce a wide variety of actions, thereby affecting several ionic channels and a multitude of receptors and enzymes. Intrathecal α2-adrenergic receptor agonists produce pronounced analgesia, and amiloride modulates α2-adrenergic receptor agonist binding and function, acting via the allosteric site on the α2A-adrenergic receptor.OBJECTIVES: To investigate the antinociceptive interaction of intrathecal amiloride and the α2-adrenoceptor agonist tizanidine using a rat formalin test.METHODS: Sprague-Dawley rats were chronically implanted with lumbar intrathecal catheters and were tested for paw flinching using formalin injection. Biphasic painful behaviour was recorded. Amiloride, tizanidine or an amiloride-tizanidine mixture was administered 10 min before formalin injection. To characterize any interactions, isobolographic analysis was performed. The effects of a pretreatment using intrathecally administered yohimbine was also tested.RESULTS: Intrathecally administered amiloride (12.5 μg to 100 μg) and tizanidine (0.5 μg to 5 μg), given separately, produced a significant dose-related suppression of the biphasic responses in the formalin test. Isobolographic analysis revealed that the combination of intrathecal amiloride and tizanidine synergistically reduced phase I and II activities. Intrathecally administered yohimbine antagonized or attenuated the antinociceptive effect of amiloride, tizanidine and the amiloride-tizanidine mixture. Intrathecally administered amiloride synergistically interacts with tizanidine to reduce the nociceptive response in the formalin test, most likely by activating α2-adrenoceptors in the spinal cord.CONCLUSIONS: Although intrathecal tizanidine produced pronounced analgesia, antinociceptive doses of intrathecal tizanidine also produced several side effects, including bradycardia and sedation. Amiloride produced antinociceptive action against the thermal nociceptive test without side effects in rats.

Nitrous Oxide Activates GABAergic Neurons in the Spinal Cord in Fischer Rats

2001 ◽  
Vol 95 (2) ◽  
pp. 463-469 ◽  
Author(s):  
Toshikazu Hashimoto ◽  
Mervyn Maze ◽  
Yoko Ohashi ◽  
Masahiko Fujinaga
Keyword(s):  
Spinal Cord ◽  
Nitrous Oxide ◽  
Glutamic Acid ◽  
Glutamic Acid Decarboxylase ◽  
Antinociceptive Effect ◽  
Gabaergic Neurons ◽  
Acid Decarboxylase ◽  
Noradrenergic Neurons ◽  
Neuronal Activation ◽  
Fischer Rats

Background Findings to date indicate that nitrous oxide exerts its antinociceptive effect by activating descending noradrenergic neurons. The mechanism whereby descending inhibitory neurons, including noradrenergic neurons, produce antinociceptive effect remains unclear. Using c-Fos protein as a marker for neuronal activation, we examined whether spinal cord neurons activated by nitrous oxide are y-aminobutyric acid-mediated (GABAergic) neurons. Methods Adult male Fischer (a strain in which nitrous oxide shows strong antinociceptive properties) and Lewis (a strain in which nitrous oxide lacks antinociceptive properties) rats were exposed to either air (control) or nitrous oxide. Frozen sections of the spinal cord were either stained for c-Fos or double-stained for c-Fos and glutamic acid decarboxylase (a rate-limiting enzyme for GABA synthesis) and analyzed by standard or confocal microscopy. Results In Fischer rats, 90 min of 75% N2O administration increased the number of c-Fos-positive cells in the spinal cord approximately threefold as compared with the control group. The c-Fos-positive cells induced by nitrous oxide were almost entirely colocalized with glutamic acid decarboxylase-positive cells. In contrast, exposure did not change the number of c-Fos-positive cells in the spinal cord in Lewis rats. Conclusions Exposure to nitrous oxide activates GABAergic neurons in the spinal cord. The dose-dependence of GABAergic neuronal activation in the Fischer rats and its absence in the Lewis rat correlate with antinociceptive responses previously reported in these same circumstances. Together, we interpret these data to indicate that activation of GABAergic neurons in the spinal cord are involved in the antinociceptive action of nitrous oxide.

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