Injection Of Yohimbine Research Articles

Noradrenergic modulation of stress induced catecholamine release: Opposing influence of FG7142 and yohimbine.

Life stress modulates decision making, particularly in the face of risk, in some cases prompting vulnerable populations to make suboptimal, life-altering choices. In the brain, stress is known to alter the extracellular release of catecholamines in structures such as basolateral amygdala (BLA) and nucleus accumbens (NAc), but the relationship between catecholamines and decision-making behavior under stress has not been systemically explored. We developed an operant touchscreen decision-making task for rats comprising elements of loss aversion and risk seeking behavior. Rats were first injected systemically with an adrenergic -receptor agonist (guanfacine) and antagonist (yohimbine), as well as a partial inverse GABAA agonist, FG 7142, known to induce anxiety and stress related physiological responses in a variety of species, including humans. We then used fiber photometry to monitor NE in the basolateral amygdala (BLA), and DA activity in the nucleus accumbens (NAc) while animals engaged in decision-making and following systemic injections of FG 7142 and yohimbine. Neither yohimbine nor guanfacine had any impact on decision making strategy but altered motivational state with yohimbine making the animal almost insensitive to the reward outcome. The pharmacological induction of stress with FG 7142 biased the rats' decisions towards safety, but this bias shifted toward risk when co-treated with yohimbine. In the BLA and NAc, the FG 7142 altered catecholamine release, with systemic yohimbine producing opposing effects on NE and DA release. Stress induced changes in catecholamine release in the BLA and NAc can directly influence loss sensitivity, decisions and motivation, which can be modulated by the adrenoreceptor antagonist, yohimbine.

The Dual Cardiovascular Effect of Centrally Administered Clonidine: A Comparative Study between Pentobarbital- and Ketamine/Xylazine-Anesthetized Rats

The administration of the α2-adrenergic receptor agonist clonidine via intracerebroventricular route produces hypotension in pentobarbital-anesthetized rats and pressor responses in conscious normotensive rats. We explored the impact of different anesthetics on the central nervous system-dependent cardiovascular effects of clonidine. Normotensive male Wistar rats with guide cannulas previously implanted in the cerebroventricular system were anesthetized with pentobarbital or ketamine/xylazine and prepared for blood pressure measurement. The animals received intracerebroventricular injections of 10 μg clonidine or 0.6 μg dexmedetomidine, and the effects on the systolic, diastolic, mean arterial pressure, and heart rate were evaluated. The influence of 5 μg yohimbine, a selective α2-adrenergic receptor antagonist, was also assessed. The i.c.v. microinjection of clonidine decreased all three components of systemic arterial pressure and the heart rate of pentobarbital-anesthetized rats. On the other hand, clonidine increased the blood pressure and generated a less intense reduction in the heart rate of ketamine/xylazine-anesthetized rats. The pressor and bradycardic effects of clonidine in ketamine/xylazine-anesthetized animals were reproduced by dexmedetomidine, a more selective α2-adrenergic receptor agonist. Notably, the previous intracerebroventricular injection of yohimbine significantly inhibited the hypertensive effect of clonidine and dexmedetomidine. This study discloses that while normotensive rats anesthetized with pentobarbital show hypotensive responses, the stimulation of α2-adrenergic receptors increases the blood pressure in rats under ketamine/xylazine-induced anesthesia, reproducing the effects seen in conscious normotensive animals. Recognizing the mechanisms involved in these differences may allow us to understand better the final effects of clonidine and other α2-adrenergic receptor agonists in the central nervous system, contributing to the repurposing of these drugs.

Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn

BackgroundThe noradrenergic neurons of locus coeruleus (LC) project to the spinal dorsal horn (SDH), and release norepinephrine (NE) to inhibit pain transmission. However, its effect on pathological pain and the cellular mechanism in the SDH remains unclear. This study aimed to explore the analgesic effects and the anti-neuroinflammation mechanism of LC-spinal cord noradrenergic pathway (LC:SC) in neuropathic pain (NP) mice with sciatic chronic constriction injury.MethodsThe Designer Receptors Exclusively Activated by Designer Drugs (DREADD) was used to selectively activate LC:SC. Noradrenergic neuron-specific retro–adeno-associated virus was injected to the spinal cord. Pain threshold, LC and wide dynamic range (WDR) neuron firing, neuroinflammation (microglia and astrocyte activation, cytokine expression), and α2AR expression in SDH were evaluated.ResultsActivation of LC:SC with DREADD increased the mechanical and thermal nociceptive thresholds and reduced the WDR neuron firing. LC:SC activation (daily, 7 days) downregulated TNF-α and IL-1β expression, upregulated IL-4 and IL-10 expression in SDH, and inhibited microglia and astrocytes activation in NP mice. Immunofluorescence double staining confirmed that LC:SC activation decreased the expression of cytokines in microglia of the SDH. In addition, the effects of LC:SC activation could be reversed by intrathecal injection of yohimbine. Immunofluorescence of SDH showed that NE receptor α2B-AR was highly expressed in microglia in CCI mice.ConclusionThese findings indicate that selective activation of LC:SC alleviates NP in mice by increasing the release of NE and reducing neuroinflammation of astrocytes and microglia in SDH.

Effects of intraperitoneal and intracerebroventricular injection of cinnamaldehyde and yohimbine on blood glucose and serum insulin concentrations in ketamine-xylazine induced acute hyperglycemia.

This study was designed to investigate the effects of peripheral [intraperitoneal (IP)] and central [intracerebroventricular (ICV)] administration of cinnamaldehyde on concentrations of blood glucose and serum insulin in the acute hyperglycemia induced by ketamine/xylazine. Yohimbine (a α2-adrenoceptor antagonist) was used alone and in combination with cinnamaldehyde to explore the α2-adrenergic receptor contribution. A total of 48 rats were divided into eight groups with six rats in each for IP administration of normal saline, vehicle, cinnamaldehyde (25.00, 50.00 and 100 mg kg-1), yohimbine (0.50 and 2.00 mg kg-1) and cinnamaldehyde plus yohimbine. These rats were used again for ICV administration 15 days after the completion of IP experiment. During this 15 days period, the lateral ventricle of the brain was surgically cannulated for ICV administration of normal saline, vehicle, cinna-maldehyde (25.00, 50.00 and 100 µg per rat), yohimbine (5.00 and 20.00 µg per rat) and cinnamaldehyde plus yohimbine. Blood glucose levels were measured from tail blood using a glucometer and serum insulin concentrations were determined via enzyme-linked immune-sorbent assay kit. The increased levels of blood glucose and the decreased concentrations of serum insulin were significantly decreased and increased, respectively, by separate and combined IP and ICV administrations of cinnamaldehyde and yohimbine. The systemic effects of these chemical compounds were significantly greater than the central ones. Based on the results, it can be argued that cinnamaldehyde has a potential to induce anti-hyperglycemic and antihypoinsulinemic effects. Peripheral and central α2-adrenegic receptors might be involved in these effects of cinnamaldehyde.

Effect of intraperitoneally administered propentofylline in a rat model of postoperative pain.

BackgroundIn this study, we sought to evaluate whether systemic propentofylline (PPF) has antiallodynic effects in a rat model of postoperative pain, and to assess the mechanism involved.MethodsAfter plantar incision, rats were intraperitoneally injected with various doses of PPF to evaluate its antiallodynic effect. To investigate the involved mechanism, rats were intraperitoneally injected with yohimbine, dexmedetomidine, prazosin, naloxone, atropine or mecamylamine, following the incision of the rat hind paws, and then PPF was administered intraperitoneally. The mechanical withdrawal threshold (MWT) was evaluated using von Frey filaments at various time points and serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were measured to determine the inflammatory response level.ResultsMWT was significantly increased after intraperitoneal injection of 30 mg/kg of PPF when compared with the control group. Injection of PPF and yohimbine, atropine or mecamylamine showed significant decreases in the MWT, while injection of PPF and dexmedetomidine showed a significant increase. Systemic administration of PPF inhibited the post-incisional increase in serum level of TNF-α and IL-1β.ConclusionsSystemic administration of PPF following surgery presented antiallodynic effects in a rat model of postoperative pain. The antiallodynic effects against mechanical allodynia could be mediated by α-adrenergic and cholinergic receptors.

Effect of curcumin, an active substance of turmeric, on acute hyperglycemia induced by ketamine-xylazine: role of α2-adrenergic receptor.

Objective- Medicinal plants and their active constituents are frequently used components for treating hyperglycemia. In the present study, the effect of curcumin was investigated on acute hyperglycemia and hyperinsulinemia induced by ketamine-xylazine in rats. To explore the possible mechanism, yohimbine (an α2-adrenergic receptor antagonist) was also used. Design- An experimental study. Animals– Forty-eight healthy male Wistar rats. Procedures– Rats were divided into eight groups with six rats in each group to receive intraperitoneal injection of normal saline, oral administration of curcumin (12.5, 50 and 200 mg/kg), intraperitoneal injection of yohimbine (0.5 and 2 mg/kg), and oral administration of curcumin (12.5 mg/kg) plus intraperitoneal injection of yohimbine (0.5 mg/kg). After these treatments, ketamine (100 mg/kg) and xylazine (10 mg/kg) were intraperitoneally administered to all groups. Blood glucose concentration was measured at 60 and 5 min before and at, 30, 60, 90 and 120 min after ketamine-xylazine injection. Serum insulin concentration was measured by ELISA kit at the end of experiment. Results- Ketamin-xylazine increased blood glucose and decreased serum insulin. Curcumin lowered increased blood glucose and increased decreased serum insulin. Yohimbine prevented the hyperglycemia and hypoinsulinemia induced by ketamin-xylazine produced the same results as curcumin. Low doses of curcumin and yohimbine induced documented hypoglycemic and hyperinsulinemic effects. Conclusion and Clinical Relevance- Based on the results, it is concluded that curcumin improves hyperglycemia and hypoinsulinemia induced by ketamine- xylazine and α2-adrenergic receptor may involve in this effect.

Involvement of descending pain control system regulated by orexin receptor signaling in the induction of central post-stroke pain in mice

Central post-stroke pain (CPSP) is a type of neuropathic pain for which the mechanism and relevant drug pathways remain unknown. Recently, it was reported that intracerebroventricular (ICV) administration of orexin-A suppresses pain and ischemia. In this study, we tested the role of orexin-A in CPSP induction in mice. Male ddY mice were subjected to 30 min of bilateral carotid artery occlusion (BCAO). CPSP was assessed by von Frey test. Colocalization of orexin 1 receptor (OX1R) with various neuron markers were determined by double-immunofluorescence. The hindpaw withdrawal responses to mechanical stimuli were significantly increased 3 days post-BCAO compared with those of sham groups. ICV injection of orexin-A dose-dependently suppressed BCAO-induced mechanical allodynia. These effects were inhibited by pre-treatment with SB334867 (an OX1R antagonist; ICV injection), yohimbine (a noradrenaline α2 receptor antagonist; intrathecal (IT) injection), and WAY100635 (a serotonin 5-HT1A receptor antagonist; IT injection), but not TCS OX2 29 (an OX2R antagonist; ICV injection). OX1R colocalized with TH (a noradrenergic neuron marker) and TPH (a serotonergic neuron marker) in the locus ceruleus (LC) and the rostral ventromedial medulla (RVM), respectively. The number of c-Fos positive cells in the LC and the RVM of BCAO mice was increased at 90 min after ICV injection of orexin-A compared to saline group. These results indicate that orexin-A/OX1R signaling plays an important role through activation of the descending pain control system in the induction of CPSP in mice.

Escalated Alcohol Self-Administration and Sensitivity to Yohimbine-Induced Reinstatement in Alcohol Preferring Rats: Potential Role of Neurokinin-1 Receptors in the Amygdala

Genetic factors significantly contribute to the risk for developing alcoholism. To study these factors and other associated phenotypes, rodent lines have been developed using selective breeding for high alcohol preference. One of these models, the alcohol preferring (P) rat, has been used in hundreds of preclinical studies over the last few decades. However, very few studies have examined relapse-like behavior in this rat strain. In this study, we used operant self-administration and yohimbine-induced reinstatement models to examine relapse-like behavior in P rats. Our previous work has demonstrated that P rats show increased expression of the neurokinin-1 receptor (NK1R) in the central nucleus of the amygdala (CeA), and this functionally contributes to escalated alcohol consumption in this strain. We hypothesized that P rats would show increased sensitivity to yohimbine-induced reinstatement that is also mediated by NK1R in the CeA. Using Fos staining, site-specific infusion of NK1R antagonist, and viral vector overexpression, we examined the influence of NK1R on the sensitivity to yohimbine-induced reinstatement of alcohol seeking. We found that P rats displayed increased sensitivity to yohimbine-induced reinstatement as well as increased neuronal activation in the CeA after yohimbine injection compared to the control Wistar strain. Intra-CeA infusion of NK1R antagonist attenuates yohimbine-induced reinstatement in P rats. Conversely, upregulation of NK1R within the CeA of Wistar rats increases alcohol consumption and sensitivity to yohimbine-induced reinstatement. These findings suggest that NK1R upregulation in the CeA contributes to multiple alcohol-related phenotypes in the P rat, including alcohol consumption and sensitivity to relapse.

α2 Receptors in the lateral parabrachial nucleus generates the pressor response of the cardiovascular chemoreflex, effects of GABAA receptor

The lateral parabrachial nucleus (LPBN) is a pontine area involved in cardiovascular chemoreflex. This study was performed to find the effects of reversible synaptic blockade of the LPBN on the chemoreflex responses, and to find the roles of GABAA receptor and α2-adenoreceptor (α2-AR) in chemoreflex. It also aimed to seek possible interaction between GABA and noradrenergic systems of the LPBN in urethane-anesthetized male rats. Cardiovascular chemoreflex was activated by intravenous injection of potassium cyanide (KCN, 80 μg/kg). The cardiovascular responses of chemoreflex were evaluated before (control), 5 and 15 min after microinjection of each drug (100 nl) into the LPBN.Microinjections of cobalt chloride (5 mM), a reversible synaptic blocker, into the LPBN greatly attenuated the chemoreflex pressor and bradycardic responses indicating that the LPBN plays a main role in chemoreflex. Local injection of yohimbine (10 nmol), an α2-AR antagonist, attenuated the pressor response with no effect on bradycardic response, suggesting that α2-adrenoreceptors are involved in producing the pressor response of the chemoreflex. Microinjection of bicuculline methiodide (BMI, 100 pmol), a GABAA antagonist, into the LPBN augmented the pressor response and attenuated the bradycardic response, indicating that GABA inhibits the sympathetic output to the heart and vasculature. Sequential injection of yohimbine and BMI had no significant effect on the pressor response but attenuated the bradycardia.In conclusion, the LPBN is essential for the chemoreflex responses. The pressor response of the chemoreflex, at least partly, is produced by α2- adenoreceptors. GABA in the LPBN inhibits the cardiovascular system. Finally, there is no interaction between GABAergic and adrenergic neurons of the LPBN in producing the cardiovascular chemoreflex.

The neurokinin-1 receptor mediates escalated alcohol intake induced by multiple drinking models

We have previously demonstrated that the neurokinin-1 receptor (NK1R) is upregulated in the central nucleus of the amygdala of alcohol preferring (P) rats and that this receptor mediates escalated alcohol consumption in this strain. However, it is unclear if non-genetic models of escalated consumption are also mediated by NK1R signaling, and if so, what brain regions govern this effect. In the experiments presented here, we use two methods of inducing escalated alcohol intake in outbred Wistar rats: yohimbine pretreatment and intermittent alcohol access (Monday, Wednesday, and Friday availability; 20% alcohol). We found that escalated alcohol consumption induced by both yohimbine injection and intermittent access is attenuated by systemic administration of the NK1R antagonist L822429. Also, when compared to continuous alcohol access or access to water alone, NK1R expression was increased in the nucleus accumbens (NAC) and dorsal striatum, but not the amygdala. Escalated consumption induced by intermittent access was attenuated when the NK1R antagonist L822429 was infused directly into the dorsal striatum, but not when infused into the NAC. Taken together, these results suggest that NK1R upregulation contributes to escalated alcohol consumption that is induced by genetic selection, yohimbine injection, and intermittent access. However there is a dissociation between the regions involved in these behaviors with amygdalar upregulation contributing to genetic predisposition to escalated consumption and striatal upregulation driving escalation that is induced by environmental exposures.

A Model of Δ9-Tetrahydrocannabinol Self-administration and Reinstatement That Alters Synaptic Plasticity in Nucleus Accumbens

BackgroundCannabis is the most widely used illicit drug, but knowledge of the neurological consequences of cannabis use is deficient. Two primary components of cannabis are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We established a THC+CBD model of self-administration and reinstated drug seeking to determine if, similar to other addictive drugs, cannabis produces enduring synaptic changes in nucleus accumbens core (NAcore) thought to contribute vulnerability to drug reinstatement. MethodsSprague Dawley rats were trained to self-administer THC+CBD (n = 165) or were used as vehicle self-administering control animals (n = 24). Reinstatement was initiated by context, cues, drug priming, and stress (yohimbine injection). Enduring neuroadaptations produced by THC+CBD self-administration were assayed using four measures: dendritic spine morphology, long-term depression, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartate ratios, and behavioral pharmacology. ResultsWe described a novel rodent model of cannabis relapse involving intravenous THC+CBD self-administration and drug seeking induced by conditioned context, cues, and stress. Cued reinstatement of THC+CBD seeking depended on a sequence of events implicated in relapse to other addictive drugs, as reinstatement was prevented by daily treatment with N-acetylcysteine or acute intra-NAcore pretreatment with a neuronal nitric oxide synthase or matrix metalloprotease-9 inhibitor, all of which normalize impaired glutamate homeostasis. The capacity to induce N-methyl-D-aspartate long-term depression in NAcore medium spiny neurons was abolished and dendritic spine density was reduced, but alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartate ratio was unaltered in THC+CBD-trained animals, akin to opioids, but not to psychostimulants. ConclusionsWe report enduring consequences of THC+CBD use on critical relapse circuitry and synaptic physiology in NAcore following rat self-administration and provide the first report of cue- and stress-induced reinstatement with this model.

Regulation of eye and jaw colouration in three-spined stickleback Gasterosteus aculeatus.

Fish can change their skin and eye colour for background matching and signalling. Males of Gasterosteus aculeatus develop ornamental blue eyes and a red jaw during the reproductive season, colours that are further enhanced during courtship. Here, the effects of different hormones on physiological colour changes in the eyes and jaws of male and female G. aculeatus were investigated in vitro. In an in vivo experiment, G. aculeatus were injected with a receptor blocker of a pivotal hormone (noradrenaline) that controls colour change. In males, noradrenaline had aggregating effects on melanophore and erythrophore pigments resulting in blue eyes and a pale jaw, whereas melanocyte-concentrating hormone (MCH) and melatonin resulted in a pale jaw only. When noradrenalin was combined with melanocyte stimulating hormone (MSH) or prolactin, the jaw became red, while the eyes remained blue. In vivo injection of yohimbine, an alpha-2 adrenoreceptor blocker, resulted in dispersion of melanophore pigment in the eyes and inhibited the blue colouration. Altogether, the data suggest that noradrenalin has a pivotal role in the short-term enhancement of the ornamental colouration of male G. aculeatus, potentially together with MSH or prolactin. This study also found a sex difference in the response to MCH, prolactin and melatonin, which may result from different appearance strategies in males, versus the more cryptic females.

Noradrenaline induces peripheral antinociception by endogenous opioid release.

The aim of this study was to investigate this involvement in not inflammatory model of pain and which opioid receptor subtype mediates noradrenaline-induced peripheral antinociception. Noradrenaline is involved in the intrinsic control of pain-inducing pro-nociceptive effects in the primary afferent nociceptors. However, inflammation can induce various plastic changes in the central and peripheral noradrenergic system that, upon interaction with the immune system, may contribute, in part, to peripheral antinociception. Hyperalgesia was induced by intraplantar injection of prostaglandin E2 (PGE2, 2μg) into the plantar surface of the right hind paw and the paw pressure test to evaluated the hyperalgesia was used. Noradrenaline (NA) was administered locally into right hind paw of Wistar rat (160-200g) alone and after either agents, α2-adrenoceptor antagonist yohimbine, α1-adrenoceptor antagonist prazosin, β-adrenoceptor antagonist propranolol, μ-opioid antagonist clocinnamox, δ-opioid antagonist naltrindole and κ-opioid antagonist nor-binaltorfimina. In addition, the enkephalinase inhibitor bestatin was administered prior to NA low dose. Intraplantar injection of NA induced peripheral antinociception against hyperalgesia induced by PGE2. This effect was reversed, in dose dependent manner, by intraplantar injection of yohimbine, prazosin, propranolol, clocinnamox and naltrindole. However, injection of nor-binaltorfimina did not alter antinociception of NA after PGE2 hyperalgesia. Bestatin intensified the antinociceptive effects of low-dose of NA. Besides the α2-adrenoceptor, the present data provide evidence that, in absence of inflammation, NA activating α1 and β-adrenoceptor induce endogenous opioid release to produce peripheral antinociceptive effect by μ and δ opioid receptors.

α2-Adrenoceptor-ir neurons’ density changes after single dose of clonidine and yohimbine administration in the hippocampus of male rat

ABSTRACTObjective: Despite the important role of α2-adrenoceptors in pain modulation processes, the impact of administration of α2-adrenoceptor agonist and antagonist on the density of hippocampal α2-adrenoceptor-immunoreactive neurons has not been investigated. Therefore, we aimed to determine the effect of single doses of clonidine and yohimbine on the density of α2-adrenoceptor-immunoreactive neurons in rat hippocampus.Materials and Methods: Adult male Wistar rats received a single dose of clonidine (0.7 mg/kg) alone or 5 min after intraperitoneal (1 mg/kg) and/or intracerebroventricular (5 µg/kg) injection of yohimbine. After histological processing, neurons with α2-adrenoceptor immunoreactivity were identified and counted through immunohistochemical analysis of hippocampal regions.Results: Clonidine slightly increased the number of α2-adrenoceptor-immunoreactive neurons in the hippocampal subregions compared with the normal saline group. Intraperitoneal injection of yohimbine followed by injection of clonidine significantly increased the number of α2-adrenoceptor-immunoreactive neurons in subregions cornu ammonis 1 (CA1) and cornu ammonis 3 (CA3). Intracerebroventricular injection of yohimbine after injection of clonidine significantly reduced the number of α2-adrenoceptor-immunoreactive neurons in all hippocampal subregions.Conclusion: The present study demonstrates that intraperitoneal administration of α2-adrenoceptor agonist clonidine increases the density of α2-adrenoceptor-immunoreactive neurons in rat hippocampus, while intracerebroventricular injection of yohimbine decreases the density of these neurons.

Изменение специфического связывания [N-метил-<sup>3</sup>H]флунитразепама при воздействии анксиогенами

Изучено влияние лекарственных препаратов и фармакологических соединений, обладающих анксиогенными свойствами: йохимбин, кофеин, производное β-карболинов — соединение β-ССВ на специфическое связывание полного агониста бензодиазепинового участка ГАМКА рецептора [N-метил-3H]флунитразепама. Кофеин в дозе 100 мг/кг, n-бутил-β-карболин-3 карбоксилат (β-ССВ) в дозе 3 мг/кг и йохимбин в дозе 5 мг/кг вызывали анксиогенный эффект у мышей линии Balb/c и C57Bl/6. Анксиогенная активность кофеина, β-ССВ и йохимбина сопряжена с падением уровня бензодиазепиновой рецепции.

Influences of intraperitoneal injection of dexmedetomidine on activation of spinal glial cells in diabetic neuropathic pain rats

Objective Exploring the influences of intraperitoneal injection of dexmedetomidine(Dex) on activation of spinal glial cells and expression of inflammatory factors in rats with diabetic neuropathic pain(DNP). Methods Thirty two health male SD rats, weight 180-200 g, were divided into four groups (n=8) according the random number table method. The four groups included the control group(group C), diabetic neuropathic pain group(group DNP), group Dex and α2 receptor antagonist group(group YOH). Streptozotocin(STZ) was used to establish the DNP model in rats. Starting from 28 d after STZ injection, Dex group was given intraperitoneal injection of Dex(50 μg/kg) for consecutive 7 d, while group YOH was given intraperitoneal injection of Yohimbine(0.1 mg/kg) 30 min before intraperitoneal injection of Dex(50 μg/kg) for consecutive 7 d. Mechanical withdrawal threshold (MWT) was determined in each group of rats 29-35 d after STZ injection. Rats were sacrificed after MWT detection on 35 d. Immunofluorescence double-staining was used to detect activation of microglia and astrocytes in rat spinal cord of each group. ELISA was used to measure TNF-α and IL-1 expression in rat spinal cord of each group. Results Compared with group C, rat body weights were decreased while blood glucose values were increased in group DNP, group Dex and group YOH(P 0.05). Compared with group C, MWT at all time points decreased in group DNP and group YOH(P 0.05). Conclusions Dex can relieve hyperalgesia in rats with diabetic neuropathy pain. The underlying mechanism may be related to inhibition of microglia activation and reduction of the inflammatory reaction in spinal cord. Key words: Dexmedetomidine; Diabetic neuropathic pain; Microglia; Astrocyte; Inflammatory reaction

Effects of α2A Adrenoceptors on Norepinephrine Secretion from the Locus Coeruleus during Chronic Stress-Induced Depression.

Chronic stressors can often lead to the development of psychological disorders, such as depression and anxiety. The locus coeruleus (LC) is a stress sensitive brain region located in the pons, with noradrenergic neurons that project to the hypothalamus, especially the paraventricular nucleus (PVN) of the hypothalamus. The purpose of this paper is to better understand how alpha 2A-adrenoceptors (α2A-ARs) and LC-hypothalamus noradrenergic system participate in the pathophysiological mechanism of depression. In vivo norepinephrine (NE) release in the PVN triggered by electrical stimulation in the LC was detected with carbon fiber electrodes in depression model of rats induced by chronic unpredictable mild stress (CUMS). Also, the extracellular level of NE in the PVN was measured by microdialysis in vivo without any stimulation in the LC. The alpha 2-adrenoceptor (α2-AR) antagonist yohimbine and α2A-ARs antagonist BRL-44408 maleate were systemically administered to rats to determine the effects of α2A-ARs on NE release in the PVN. The peak value of elicited NE release signals in the PVN induced by electrical stimulation in the LC in the CUMS rats were lower than that in the control rats. The extracellular levels of NE in the PVN of the CUMS rats were significantly less than that of the control rats. Intraperitoneal injection of yohimbine or BRL-44408 maleate significantly potentiated NE release in the PVN of the CUMS rats. The CUMS significantly increased protein expression levels of α2A-AR in the hypothalamus, and BRL-44408 maleate significantly reversed the increase of α2A-AR protein expression levels in the CUMS rats. Our results suggest that the CUMS could significantly facilitate the effect of α2-adrenoceptor-mediated presynaptic inhibition and decrease the release of NE in the PVN from LC. Blockade of the inhibitory action of excessive α2A-adrenergic receptors in the CUMS rats could increase the level of NE in the PVN, which is effective in the treatment of depressive disorders.

Involvement of histaminergic and noradrenergic receptors in the oxytocin-induced food intake in neonatal meat-type chicks.

Oxytocin neurons have a physiological role in food intake and energy balance. Several studies have shown that central histaminergic and adrenergic systems synapse on oxytocin neurons but there is no information for their interaction on food intake regulation in birds. The purpose of this study was to examine the effects of intracerebroventricular (ICV) injection of α-fluoromethylhistidine (α-FMH, histidine decarboxylase inhibitor), chlorpheniramine (histamine H1 receptors antagonist), famotidine (histamine H2 receptors antagonist), thioperamide (histamine H3 receptors antagonist), prazosin (α1 receptor antagonist), yohimbine (α2 receptor antagonist), metoprolol (β1 adrenergic receptor antagonist), ICI 118,551 (β2 adrenergic receptor antagonist) and SR59230R (β3 adrenergic receptor antagonist) on oxytocin-induced hypophagia in 3-h food-deprived (FD3) neonatal broiler chicken. In Experiment 1, 3h-fasted chicks were given an ICV injection of saline, α-FMH (250nmol), oxytocin (10μg) and co-injection of α-FMH+oxytocin. Experiments 2-9 were similar to experiment 1 except birds were injected with chlorpheniramine (300nmol), famotidine (82nmol), thioperamide (300nmol), prazosin (10nmol), yohimbine (13nmol), metoprolol (24nmol), ICI 118,551(5nmol) and SR59230R (20nmol) instead of α-FMH, respectively. After injection cumulative food intake was measured until 120min post injection. According to the results, ICV injection of oxytocin significantly decreased food intake in broiler chickens (P<0.001). ICV injection of α-FMH significantly attenuated hypophagic effect of oxytocin (P<0.001). Also, co-injection of chlorpheniramine plus oxytocin significantly decreased the effect of oxytocin on food intake (P<0.001). Co-administration of thioperamide and oxytocin significantly amplified hypophagic effect of oxytocin in chickens (P<0.001). In addition, ICI 118,551 attenuated hypophagic effect of oxytocin (P<0.001); while famotidine, prazosin, yohimbine, metoprolol and SR59230R had no effect on oxytocin- induced food intake in FD3 broiler chickens. These results suggest that the effect of oxytocin on food intake is probably mediated by histaminergic (via H1 and H3 receptors) and noradrenergic (via β2 receptors) systems in broiler chickens.

Cocaine self-administration and reinstatement in female rats selectively bred for high and low voluntary running

BackgroundPrevious research has found that rats behaviorally screened for high (vs. low) wheel running were more vulnerable to cocaine abuse. To assess the extent to which a genetic component is involved in this drug-abuse vulnerability, rats selectively bred for high or low voluntary running (HVR or LVR, respectively) were examined for differences in cocaine seeking in the present study. MethodsFemale rats were trained to lever press for food and then were assessed for differences in acquisition of cocaine (0.4mg/kg; i.v.) self-administration across 10 sessions. Once acquired, rats self-administered cocaine for a 14-day maintenance phase, followed by a 14-day extinction phase when cocaine was no longer available. Subsequently, reinstatement of cocaine seeking was examined with priming injections of cocaine (5, 10 & 15mg/kg), caffeine (30mg/kg), yohimbine (2.5mg/kg) and cocaine-paired cues. ResultsA greater percentage of LVR rats met the acquisition criteria for cocaine self-administration and in fewer sessions than HVR rats. No differences in responding for cocaine were observed between phenotypes during maintenance. However, during extinction LVR rats initially responded at higher rates and persisted in cocaine seeking for a greater number of sessions. No phenotype differences were observed following drug and cue-primed reinstatement of cocaine seeking. ConclusionsIn general, LVR rats were more sensitive to the reinforcing effects of cocaine than HVR rats during periods of transition into and out of cocaine self-administration. Thus, LVR rats sometimes showed a greater vulnerability cocaine seeking than HVR rats.

Interaction Between Nociceptin/Orphanin FQ and Adrenergic System on Food Intake in Neonatal Chicken

The information emerging from the studies demonstrates adrenergic system and nociceptin/orphanin FQ (N/OFQ) play a crucial role on appetite regulation but there is no information for their interaction. The purpose of this study was to examine the effects of intracerebroventricular (ICV) injection of prazosin (α1 receptor antagonist), yohimbine (α2 receptor antagonist), metoprolol (β1 adrenergic receptor antagonist), ICI 118,551 (β2 adrenergic receptor antagonist) and SR59230R (β3 adrenergic receptor antagonist) on N/OFQ-induced hyperphagia by 3-h food-deprived neonatal broiler chicken. In experiment 1, chicken injected with saline, prazosin (10 nmol), N/OFQ (16 nmol) and co-injection of prazosin + N/OFQ. In experiment 2, ICV injection of saline, yohimbine (13 nmol), N/OFQ (16 nmol) and yohimbine + N/OFQ applied to the birds. In experiment 3, injections were saline, metoprolol (24 nmol), N/OFQ (16 nmol) and metoprolol + N/OFQ. In experiment 4, the birds received ICV injection of saline, ICI 118,551 (5 nmol), (C) N/OFQ (16 nmol) and co-administration of ICI 118,551 + N/OFQ. In experiment 5, chicken injected with saline, SR59230R (20 nmol), N/OFQ (16 nmol) and SR59230R + N/OFQ. Then, cumulative food intake was recorded until 120 min after injection. According to the results, ICV injection of N/OFQ significantly increased food intake (P 0.05). These results suggest that the effect of N/OFQ on cumulative food intake is mediated via β2 adrenergic receptors in neonatal chicken.