Search

Objective: In this neurophysiological study in healthy humans, we assessed how central sensitization induced by either high-frequency stimulation (HFS) or topical capsaicin application modulates features of the RIII reflex response. The ability of these stimuli to engage the endogenous pain modulatory system was also tested., Methods: In 26 healthy participants we elicited an RIII reflex using suprathreshold stimulation of the sural nerve. Subsequently HFS or capsaicin were applied to the foot and the RIII reflex repeated after 15 minutes. Contact heating of the volar forearm served as the heterotopic test stimulus to probe activation of the endogenous pain modulatory system., Results: HFS significantly reduced the pain threshold by 29% and the RIII reflex threshold by 20%. Capsaicin significantly reduced the pain threshold by 17% and the RIII reflex threshold by 18%. Both HFS and capsaicin left RIII reflex size unaffected. Numerical Rating Scale (NRS) pain scores elicited by the heterotopic noxious heat stimulus were unaffected by capsaicin and slightly increased by HFS., Conclusions: HFS and capsaicin similarly modulated the pain threshold and RIII reflex threshold, without a concomitant inhibitory effect of the endogenous pain modulatory system., Significance: Our neurophysiological study supports the use of the RIII reflex in investigating central sensitization in humans., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: Many studies have suggested the anti-nociceptive role for magnesium either as an adjunct for postoperative pain. Although several studies have been carried out to evaluate the anti-nociceptive effect of magnesium, there is still considerable uncertainty., Patients and Methods: Eighty patients who underwent posterior spinal fusion were randomly divided into two groups (magnesium and saline). Changes in cell count, magnesium concentration and coagulation status were assessed one hour after operation at both group and compared to baseline. At recovery room, their pain score was assessed according to 10 points visual analogue scale (VAS). Morphine consumption was evaluated at regular times after the surgery by patient controlled analgesia (PCA) device., Results: VAS scores were significantly lower in the magnesium group. Cumulative PCA morphine consumption after the surgery was significantly lower in the magnesium group. Pre and postoperative values for haemoglobin, platelet count, Prothrombin Time (PT), fibrinogen were not significantly different. There was a significant increase in activated Partial Thromboplastin Time (aPTT), International Normalized Ratio (INR), and bleeding time (BT), one hour after the operation in the magnesium group but intraoperative blood loss was similar in both groups., Conclusions: Perioperative magnesium sulfate infusion improves the postoperative analgesia, decreases the amount of morphine consumption after the operation and does not change the intraoperative bleeding in patients undergoing posterior spinal fusion surgery., (Copyright © 2020. Published by Elsevier B.V.)

Neuropathic orofacial pain conditions represent a challenge to diagnose and treat. Natural substances are promising therapeutic options for the control of pain., Aims: This study aimed to examine whether (-)-α-bisabolol (BISA), a natural terpene, can attenuate nociceptive behaviour and central sensitisation in a rodent model of trigeminal neuropathic pain., Materials and Methods: Infraorbital nerve transection (IONX) or sham operation was performed in adult male rats. Head withdrawal thresholds as a measure of facial mechanical sensitivity were tested with von Frey monofilaments applied bilaterally to the facial vibrissal pad pre-operatively (baseline) and then post-operatively before and at 60, 120, 240 and 360 min after administration of vehicle control per oris (p.o.) or BISA (200 mg/kg p.o.) (n = 8/group). Effects of BISA or vehicle on the activity of nociceptive neurons recorded in the medullary dorsal horn (MDH) were tested on post - operative day 8-10. ANOVA followed by post-hoc Bonferroni tested for statistically significant differences (p < 0.05) across study groups and time points., Key Findings: IONX animals (but not sham or naïve animals) showed post-operative facial mechanical hypersensitivity that was unaffected by vehicle. However, administration of BISA at post-operative day 7 significantly reversed the mechanical hypersensitivity in IONX rats; this effect lasted for at least 6 h. BISA also attenuated IONX-induced central sensitisation of MDH nociceptive neurons, as reflected in reversal of their reduced activation thresholds, increased responses to graded mechanical stimuli and enhanced spontaneous activity., Significance: BISA may attenuate nociceptive behaviour and central sensitisation in a rat model of acute trigeminal neuropathic pain., (Copyright © 2019 Elsevier Inc. All rights reserved.)

High level of positive affectivity acts as a protective factor against adverse effects of stress and decreases vulnerability to mood disorders and drug abuse. Fifty-kHz ultrasonic vocalizations (50-kHz USV) index the level of positive affect in the rat, whereas stable, trait-like inter-individual differences in terms of vocalization activity exist. Previously we have demonstrated that chronic stress can alter the effect of repeated amphetamine administration on 50-kHz vocalizations, and this effect is different in rats with high and low positive affectivity. In the present study it was tested whether the chronic stress effect on amphetamine-induced 50-kHz USV activity is altered by inhibition of serotonin reuptake. Male Wistar high (HC) and low (LC) 50-kHz vocalizing rats were subjected to 43-day chronic variable stress (CVS) regimen. On day 17 of the CVS, the four-week once a day fluoxetine (10 mg/kg) treatment was started. After the CVS and fluoxetine treatment, amphetamine (1 mg/kg) was daily administered for ten days and again nine days after withdrawal. Chronically stressed rats developed cross-sensitization of 50-kHz USV-s with repeated administration of amphetamine except the stressed LC rats that had not received fluoxetine. Amphetamine treatment decreased serotonin turnover in the fluoxetine-treated HC rats, but increased it in fluoxetine-treated LC rats. The effect of amphetamine on levels of amino acids in frontal cortex and hippocampus also depended on previous experience with chronic stress, repeated treatment with fluoxetine, and positive affectivity. Hence, this study provides further evidence the effects of chronic stress, psychostimulants, and a selective serotonin reuptake inhibitor are influenced by the inherent positive affectivity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Chronic cough is a significant problem, and in many patients cough remains refractive to both disease-specific therapies and current cough-suppressing medicines, creating a need for improved antitussive therapies. Most patients with chronic cough also display heightened sensitivity so that they experience a persistent sense of the need to cough, and often innocuous stimuli can trigger their coughing. This hypersensitivity underpins the newly described concept of cough hypersensitivity syndrome (CHS), a term that encapsulates the notion of common underlying mechanisms producing neuronal activation, sensitization and/or dysfunction, which are at the core of excessive coughing. Understanding these mechanisms has been a focus of recent research efforts in the field in the hope that new therapies can be developed to selectively target sensitized unproductive cough while maintaining the reflexive cough essential for airway protection. However, efforts to achieve this have been slower than expected, in part because of some significant challenges and limitations translating current cough models. In this review, we summarize recent advances in our understanding of the sensory circuits innervating the respiratory system that are important for cough, how cough sensory pathways become hypersensitive, and some of the recently described neural targets under development for treating chronic cough. We present the case that better use of current cough models or the development of new models, or both, is ultimately needed to advance our efforts to translate the discovery of basic cough mechanisms into effective medicines for treating patients with chronic cough., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

High novelty seeking increases the risk for drug experimentation and locomotor sensitization. Locomotor sensitization to psychostimulants is thought to reflect neurological adaptations that promote the transition to compulsive drug taking. Rats reared in enrichment (EC) show less locomotor sensitization when compared to rats reared in isolation (IC) or standard conditions (SC). The current research study was designed to test if novelty response contributed locomotor sensitization and more importantly, if the different housing environments could change the novelty response to protect against the development of locomotor sensitization in both adolescence and adulthood. Experiment 1: rats were tested for their response to novelty using the inescapable novelty test (IEN) and pseudorandomly assigned to enriched (EC), isolated (IC), or standard (SC) housing conditions for 30days. After housing, they were tested with IEN. Rats were then administered amphetamine (0.5mg/kg) or saline and locomotor activity was measured followed by a sensitization test 14days later. Experiment 2: rats were tested in the IEN test early adulthood and given five administrations of amphetamine (0.3mg/kg) or saline and then either stayed in or switched housing environments for 30days. Rats were then re-tested in the IEN test in late adulthood and administered five more injections of their respective treatments and tested for locomotor sensitization. Results indicate that IC and SC increased the response to novelty. EC housing decreased locomotor response to amphetamine and saline, and SC housing increased the locomotor response to amphetamine. Mediation results indicated that the late adult novelty response fully mediates the locomotor response to amphetamine and saline, while the early adulthood novelty response did not., Conclusions: Differential housing changes novelty and amphetamine locomotor response. Novelty response is altered into adulthood and provides evidence that enrichment can be used to reduce drug vulnerability., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Learned associations between environmental stimuli and rewards play a critical role in addiction. Associative learning requires alterations in sparsely distributed populations of strongly activated neurons, or neuronal ensembles. Until recently, assessment of functional alterations underlying learned behavior was restricted to global neuroadaptations in a particular brain area or cell type, rendering it impossible to identify neuronal ensembles critically involved in learned behavior., Methods: We used Fos-GFP transgenic mice that contained a transgene with a Fos promoter driving expression of green fluorescent protein (GFP) to detect neurons that were strongly activated during associative learning, in this case, context-independent and context-specific cocaine-induced locomotor sensitization. Whole-cell electrophysiological recordings were used to assess synaptic alterations in specifically activated GFP-positive (GFP+) neurons compared with surrounding nonactivated GFP-negative (GFP-) neurons 90 min after the sensitized locomotor response., Results: After context-independent cocaine sensitization, cocaine-induced locomotion was equally sensitized by repeated cocaine injections in two different sensitization contexts. Correspondingly, silent synapses in these mice were induced in GFP+ neurons, but not GFP- neurons, after sensitization in both of these contexts. After context-specific cocaine sensitization, cocaine-induced locomotion was sensitized exclusively in mice trained and tested in the same context (paired group), but not in mice that were trained in one context and then tested in a different context (unpaired group). Silent synapses increased in GFP+ neurons, but not in GFP- neurons from mice in the paired group, but not from mice in the unpaired group., Conclusions: Our results indicate that silent synapses are formed only in neuronal ensembles of the nucleus accumbens shell that are related to associative learning., (Published by Elsevier Inc.)

Background: Eating a diet high in fat can lead to obesity, chronic metabolic disease, and increased inflammation in both the central and peripheral nervous systems. Dietary supplements that are high in omega-3 polyunsaturated fatty acids can reduce or prevent these negative health consequences in rats. Eating high fat chow also increases the sensitivity of rats to behavioral effects of drugs acting on dopamine systems (e.g., cocaine), and this effect is greatest in adolescent females., Methods: The present experiment tested the hypothesis that dietary supplementation with fish oil prevents high fat chow induced increases in sensitivity to cocaine in adolescent female rats. Female Sprague-Dawley rats (post-natal day 25-27) ate standard laboratory chow (5.7% fat), high fat chow (34.4% fat), or high fat chow supplemented with fish oil (20% w/w). Cocaine dose dependently (1-17.8mg/kg) increased locomotion and induced sensitization across 6 weeks of once-weekly testing in all rats; however, these effects were greatest in rats eating high fat chow., Results: Dietary supplementation with fish oil prevented enhanced locomotion and sensitization in rats eating high fat chow. There were no differences in inflammatory markers in plasma or the hypothalamus among dietary conditions., Conclusions: These results demonstrate that dietary supplementation with fish oil can prevent high fat diet-induced sensitization to cocaine, but they fail to support the view that these effects are due to changes in proinflammatory cytokines. These data add to a growing literature on the relationship between diet and drug abuse and extend the potential health benefits of fish oil to stimulant drug abuse prevention., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The 5' adenosine monophosphate-activated protein kinase (AMPK) functions as an intracellular energy sensor that regulates and maintains energy balance. The psychostimulant drug cocaine has profound effects on behavior that are accentuated with repeated use, which is a process termed sensitization. Thus, the present study examined whether the sensitizing effects of cocaine could be observed in the AMPK system and aimed to determine whether these effects were mediated by dopamine (DA) D1 or D2 receptors. In the first set of experiments, rats were injected daily for 5days with either cocaine (15mg/kg, intraperitoneal [IP]) or saline. On the day 6, each group was divided into two subgroups and given either cocaine or saline. In the second set of experiments, rats were pretreated with SCH23390 (0.5mg/kg, IP), haloperidol (1mg/kg, IP), or both agents in combination, followed by cocaine or saline treatment. In the drug-naïve state, acute treatment with cocaine produced an increase in locomotor activity and increased AMPK phosphorylation in the frontal cortex but decreased it in the dorsal striatum. In the drug-sensitized state (following repeated treatment), the behavioral responsiveness to cocaine was augmented and accompanied by alterations in AMPK activity. The phosphorylation levels of the upstream kinases Ser-431-LKB1 and Thr-196-CaMK4 were congruent with the changes in AMPK activity. Thr-184/187-TAK1 was phosphorylated after chronic cocaine treatment in the dorsal striatum but not in the frontal cortex. The opposite effects induced by cocaine in the AMPK system in the dorsal striatum and frontal cortex may be explained by the differential activations of DA D1 and D2 receptors in these brain regions., (Copyright © 2016. Published by Elsevier Inc.)

The misuse and abuse of the psychostimulant, methylphenidate (MPD) the drug of choice in the treatment of attention deficit hyperactivity disorder (ADHD) has seen a sharp uprising in recent years among both youth and adults for its cognitive enhancing effects and for recreational purposes. This uprise in illicit use has lead to many questions concerning the long-term consequences of MPD exposure. The objective of this study was to record animal behavior concomitantly with the caudate nucleus (CN) neuronal activity following acute and repetitive (chronic) dose response exposure to methylphenidate (MPD). A saline control and three MPD dose (0.6, 2.5, and 10.0mg/kg) groups were used. Behaviorally, the same MPD dose in some animals following chronic MPD exposure elicited behavioral sensitization and other animals elicited behavioral tolerance. Based on this finding, the CN neuronal population recorded from animals expressing behavioral sensitization was also evaluated separately from CN neurons recorded from animals expressing behavioral tolerance to chronic MPD exposure, respectively. Significant differences in CN neuronal population responses between the behaviorally sensitized and the behaviorally tolerant animals were observed for the 2.5 and 10.0mg/kg MPD exposed groups. For 2.5mg/kg MPD, behaviorally sensitized animals responded by decreasing their firing rates while behaviorally tolerant animals showed mainly an increase in their firing rates. The CN neuronal responses recorded from the behaviorally sensitized animals following 10.0mg/kg MPD responded by increasing their firing rates whereas the CN neuronal recordings from the behaviorally tolerant animals showed that approximately half decreased their firing rates in response to 10.0mg/kg MPD exposure. The comparison of percentage change in neuronal firing rates showed that the behaviorally tolerant animals trended to exhibit increases in their neuronal firing rates at ED1 following initial MPD exposure and oppositely at ED10 MPD rechallenge. While the behaviorally sensitized animals in general increased in their percentage change of firing rats were observed following acute 10.0mg/kg MPD and the behaviorally sensitized 10.0mg/kg MPD animals and a robust increase in neuronal firing rates at ED1 and ED10 rechallenge. These results suggest the need to first individually analyze animal behavioral activity, and then to evaluate the neuronal responses to the drug based on the animals behavioral response to chronic MPD exposure., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Repeated high dose injections of the direct acting D1/D2 agonist apomorphine (APO) induces context specific behavioral sensitization. We assessed the effects of 2.0 mg/kg APO on open-field locomotor responses of rats over a 30 min period following either single or five daily APO injections. Acute injections increased locomotor activity, which was markedly increased in rats given 5 daily APO injections. This progressive increase in locomotion during the repeated APO treatments is indicative of behavioral sensitization. Immediately following the open-field test for the acute and the fifth apomorphine injection, the animals were euthanized and their brain tissue was prepared for immunohistochemistry. ERK immunoreactive nuclei in the medial prefrontal cortex (PFC), nucleus accumbens (NAcc), amygdala (AMYG) and lateral hypothalamus (LH) were quantified. The acute apomorphine injections increased ERK in all brain areas as compared to vehicle. Following the fifth apomorphine injection, ERK significantly increased in the PFC, decreased in the amygdala but was unchanged in the LH and NAcc. The selective increase in ERK activity in the PFC associated with behavioral sensitization, points to a possible pivotal role of the dopamine projection to the medial frontal cortex in the mediation of neural plasticity, considered to underlie the sensitization processes induced by dopaminergic drugs., (Copyright © 2013. Published by Elsevier Inc.)

The nucleus accumbens (NAc) and the ventral tegmental area (VTA) are two major areas for the mesolimbic dopaminergic system which are strongly involved in the development of behavioral sensitization. In the present study, we investigated the role of D1/D2 dopaminergic receptors within the NAc or VTA in response to sensitization to morphine by the tail-flick test as a model of acute pain. Sensitization was induced by subcutaneous (SC) injection of morphine (5 mg/kg), once daily for three days followed by 5 days free of drug. After the sensitization period, antinociceptive responses induced by an ineffective dose of morphine (1 mg/kg; SC) were obtained by the tail-flick test, and represented as maximal possible effect (%MPE). In experimental groups, D1 and D2 receptor antagonists, SCH-23390 and sulpiride (0.25, 1 and 4 μg/rat), were separately microinjected into the NAc or VTA, 10 min before morphine administration during the sensitization period, respectively. Results showed that injection of morphine during the sensitization period (development of sensitization) increased %MPE of the ineffective dose of morphine from 2.43±1.4% in naive to 47.75±4.01% in sensitized animals (P<0.001). Unilateral microinjections of different doses of the D1/D2 receptor antagonists, SCH-23390 and sulpiride, into the NAc dose-dependently decreased %MPEs in morphine-sensitized animals. Nonetheless, %MPEs were only affected by intra-VTA administration of SCH-23390 in morphine-sensitized animals (P<0.05). Our findings suggest that both the D1/D2 dopamine receptors in the NAc and the D1 receptors in the VTA may be of more important in the development of sensitization to morphine in rats., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To investigate the effects of central sensitization, elicited by intramuscular injection of capsaicin, by comparing the reflex receptive fields (RRF) of spinally-intact volunteers and spinal cord injured volunteers that present presensitized spinal nociceptive mechanisms., Methods: Fifteen volunteers with complete spinal cord injury (SCI) and fourteen non-injured (NI) volunteers participated in the experiment. Repeated electrical stimulation was applied on eight sites on the foot sole to elicit the nociceptive withdrawal reflex (NWR). RRF were assessed before, 1min after and 60min after an intramuscular injection of capsaicin in the foot sole in order to induce central sensitization., Results: Both groups presented RRF expansion and lowered NWR thresholds immediately after capsaicin injection, reflected by the enlargement of RRF sensitivity areas and RRF probability areas. Moreover, the topography of the RRF sensitivity and probability areas were significantly different in SCI volunteers compared to NI volunteers in terms of size and shape., Conclusions: SCI volunteers can develop central sensitization, despite adaptive/maladaptive changes in synaptic plasticity and lack of supraspinal control., Significance: Protective plastic mechanisms may still be functional in SCI volunteers., (Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Hippocampal long-term potentiation (LTP) is impaired following repeated morphine administration paired with a novel context. This procedure produces locomotor sensitization that can be abolished by blocking calcium (Ca(2+))-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) in the hippocampus. However, the mechanisms underlying LTP impairment remain unclear. Here, we investigate the role of N-methyl-D-aspartate receptors (NMDARs), AMPARs, and small conductance Ca(2+)-activated potassium type 2 (SK2) channels in LTP induction after context-dependent sensitization to morphine., Methods: Mice were treated with saline or escalating doses of morphine (5, 8, 10, and 15 mg/kg) every 12 hours in a locomotor activity chamber and a challenge dose of 5 mg/kg morphine was given 1 week later. After the challenge, the hippocampi were removed to assay phosphatase 2A (PP2A) activity, NMDAR, and SK2 channel synaptic expression or to perform electrophysiological recordings., Results: Impaired hippocampal LTP, which accompanied morphine-induced context-dependent sensitization, could not be restored by blocking Ca(2+)-permeable AMPARs. Context-dependent sensitization to morphine altered hippocampal NMDAR subunit composition and enhanced the SK2 channel-mediated negative feedback on NMDAR. Increased PP2A activity observed following context-dependent sensitization suggests that the potentiated SK2 channel effect on NMDAR was mediated by increased SK2 sensitivity to Ca(2+). Finally, inhibition of SK2 channel or PP2A activity restored LTP., Conclusions: Our studies demonstrate that the SK2 channel-NMDAR feedback loop plays a role in opiate-induced impairment of hippocampal plasticity and that the positive modulation of SK2 channels occurs via increases in PP2A activity. This provides further evidence that small conductance Ca(2+)-activated potassium channels play a role in drug-induced plasticity., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: In rodents, drugs of abuse induce locomotor hyperactivity, and repeating injections enhance this response. This effect, called behavioral sensitization, persists months after the last administration. It has been shown that behavioral sensitization to amphetamine develops parallel to an increased release of norepinephrine (NE) in the prefrontal cortex (PFC)., Methods: Rats and mice were repeatedly treated with amphetamine (1 or 2 mg/kg intraperitoneally, respectively) to obtain sensitized animals. The NE release in the PFC was measured by microdialysis in freely moving mice (n = 55). Activity of locus coeruleus (LC) noradrenergic neurons was determined in anaesthetized rats (n = 15) by in vivo extracellular electrophysiology. The α2A-adrenergic autoreceptor (α2A-AR) expression was assessed by autoradiography on brain slices, and Gαi proteins expression was measured by western blot analysis of LC punches., Results: In sensitized rats LC neurons had a higher spontaneous firing rate, and clonidine-an α2A-adrenergic agonist-inhibited LC neuronal firing less efficiently than in control animals. Clonidine also induced lower levels of NE release in the PFC of sensitized mice. This desensitization was maintained by a lower density of Gαi1 and Gαi2 proteins in the LC of sensitized mice rather than weaker α2A-AR expression. Behavioral sensitization was facilitated by α2A-AR antagonist, efaroxan, during amphetamine injections and abolished by clonidine treatment., Conclusions: Our data indicate that noradrenergic inhibitory feedback is impaired for at least 1 month in rats and mice repeatedly treated with amphetamine. This work highlights the key role of noradrenergic autoreceptor signaling in the persistent modifications induced by repeated amphetamine administration., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Repeated administration of the indirect dopamine receptor agonist amphetamine (AMPH) produces robust locomotor sensitization and additional behavioral abnormalities. Accumulating evidence suggests that the developmental timing of drug exposure can critically influence this effect. The present study compared the consequences of withdrawal from repeated AMPH exposure in adolescence and adulthood on information processing and locomotor sensitization in C57BL/6 mice. Animals were injected daily with AMPH (1 or 2.5 mg/kg) or vehicle on 7 consecutive days starting either from postnatal day 35 to 42, or from postnatal day 70 to 77, following which they were given a 4 week withdrawal period before behavioral and pharmacological testing commenced. We found that withdrawal from the higher dose of AMPH (2.5 mg/kg/day) given either in adolescence or adulthood similarly disrupted selective associative learning as measured by the latent inhibition paradigm. None of the AMPH withdrawal groups displayed alterations in sensorimotor gating in the form of prepulse inhibition. Withdrawal from adult AMPH exposure at both doses induced marked locomotor sensitization, whereas adolescent pre-treatment with the higher (2.5 mg/kg/day) but not lower (1 mg/kg/day) dose of AMPH potentiated the locomotor-enhancing effects of acute AMPH re-challenge. Our study suggests that withdrawal from repeated AMPH exposure in adolescence and adulthood has similar consequences on selective associative learning, but the two manipulations differ with respect to their efficacy to induce long-term locomotor sensitization to the drug. The latter finding supports the hypothesis that the precise developmental timing determines, at least in part, the impact on long-term dopamine-associated sensitization processes., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)

In recent years, evidence that sensitization of primary afferent nociceptors is an important event associated with chronic pain has been accumulating. The present study aimed to evaluate the participation of the prostaglandin and sympathetic components in the long-lasting sensitization of nociceptors induced by acute inflammation in mice. The intraplantar administration of carrageenan (100 μg) enhanced the nociceptive response to a small dose of PGE(2) (9 ng/paw) or dopamine (3 μg/paw) up to 30 days later. This long-lasting sensitization is dependent on dopaminergic and prostanoid systems, since the pre-treatment with chlorpromazine (3 μg/paw) or indomethacin (100 μg/paw), but not local (6 μg/paw) or systemic (6 mg/kg) treatment with morphine, prevented its development. In agreement with this idea, the previous intraplantar administration of hyperalgesic doses of PGE(2) or dopamine also induced long-lasting sensitization, which was fully prevented by pretreatment with EP(4) and D(1) antagonists, respectively. In summary, the present work described in mice a long-lasting sensitization of nociceptors, initiated by an acute inflammatory stimulation and dependent on dopaminergic and prostanoid systems. The present data represent new insights on the mechanisms of peripheral sensitization that could contribute to establish the basis of new therapeutic strategies for acute and chronic inflammatory pain., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Previous studies have shown that olfactory impairment by disrupting the olfactory epithelium prior to morphine administration attenuated the development addiction-related behaviors. However, it is unclear whether olfactory impairment will affect the expression of already established addiction-related behaviors. To address this issue, mice were conditioned with morphine to induce behavioral sensitization and condition placed preference (CPP). After an abstinence period, the animals were subjected to either an intranasal ZnSO(4) effusion (ZnE) or sham treatment with saline. Behavioral sensitization and CPP reinstatement were evaluated 24h later, as well as the expression of c-Fos protein, a marker of activated neural sites, in brain regions of interest. It was found that ZnE treatment attenuated morphine-induced behavioral sensitization and reinstatement of CPP. Compared to the saline-treated ones, the ZnE-treated animals showed reduced c-Fos expression in the nucleus accumbens (NAc) associated with behavioral sensitization, and in the NAc, cingulate cortex, dentate gyrus, amygdala, lateral hypothalamus and ventral tegmental area associated with CPP reinstatement. Together, these results demonstrated that acute olfactory impairment could attenuate already established addiction-related behaviors and expression of c-Fos in drug addiction related brain regions, perhaps by affecting the coordination between reward and motivational systems in the brain., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In the present study, the effects of repeated intra-ventral hippocampal (intra-VH) microinjections of nicotinic acetylcholine receptor agonist or antagonist on morphine-induced anxiolytic-like behavior were investigated in morphine-sensitized mice using elevated plus-maze. Intraperitoneal (i.p.) administration of different doses of morphine (5, 7.5 and 10mg/kg) increased the percentage of open arm time (%OAT), open arm entries (%OAE), but not locomotor activity, indicating an anxiolytic-like response to morphine. The maximum response was obtained by 7.5mg/kg of the opioid. The anxiety-like behavior which was induced by a lower dose of morphine (5mg/kg) was significantly increased in mice that had previously received once daily injections of morphine (10 and 20mg/kg, i.p.) for 3 days. It should be considered that this treatment also increased locomotor activity in morphine-sensitized mice. Furthermore, the response to an ineffective dose of morphine (5mg/kg, i.p.) in the EPM was significantly increased in the animals that had previously received nicotine for 3 days (0.1, 0.3, 0.5 and 0.7 μg/mouse; intra-VH), 5 min prior to the injections of morphine (5mg/kg/day × 3 days; i.p.). On the other hand, the increase of morphine-induced anxiolytic-like effect in animals that had previously received the 3-day morphine (20mg/kg) was dose dependently suppressed by once daily injections of mecamylamine (0.5, 1 and 2 μg/mouse/day × 3 days; intra-VH). It is important to note that repeated intra-VH administrations of the same doses of nicotine or mecamylamine alone caused no significant change in morphine (5mg/kg)-induced anxiety-like parameters in the EPM. In conclusion, it seems that morphine sensitization affects the anxiety-like behavior in the EPM and the cholinergic system in the ventral hippocampus, via nicotinic receptors, may play an important role in this effect., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Chronic use of morphine causes rewarding effects and behavioral sensitization, which may lead to the development of craving for morphine. A number of studies indicate that the NMDA receptors may be involved in these effects, especially the NR2B-containing NMDA receptors. It is also well recognized that the nucleus accumbens (NAc) and the ventral tegmental area (VTA) are involved in drug addiction, including morphine addiction., Aims: In this study, we further investigate the role of the NR2B subunit of NMDA receptors at NAc or VTA in morphine rewarding effects and behavioral sensitization., Methods and Results: The siRNA against the NR2B subunit of NMDA receptors was locally injected to decrease the expression of NR2B at NAc or posterior VTA in male Sprague-Dawley (S.D.) rats in the present study. The rats were then treated with morphine chronically. A conditioned place preference (CPP) test was used to examine the rewarding effect, and locomotor activity was measured to determine the behavioral sensitization induced by chronic morphine treatment. Results showed that morphine-induced rewarding behavior but not behavioral sensitization was abolished when the NR2B subunit of NMDA receptors at the NAc were significantly decreased. The dopamine turnover rate was not altered by the decrease of NR2B subunit at NAc., Conclusion: These findings suggest that the NR2B subunit of NMDA receptors at the NAc is involved in morphine-induced rewarding effect and may not be through directly interacting with dopamine neurons., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: The β-lactam antibiotic and glutamate transporter subtype 1 (GLT-1) activator ceftriaxone prevents relapse to cocaine-seeking and inhibits morphine-induced physical dependence and tolerance in rats, but its efficacy against amphetamine-induced behaviors is unknown., Methods: Here, we tested the hypothesis that ceftriaxone (200mg/kg, i.p.) inhibits hyperactivity produced by acute amphetamine administration (2mg/kg, i.p.) and sensitization of hyperactivity induced by repeated amphetamine exposure (2mg/kg, i.p.). For acute experiments, rats treated with ceftriaxone for 5 days were injected with amphetamine or saline on day 6., Results: Amphetamine elicited less ambulatory and stereotypical activity in ceftriaxone-treated rats than in ceftriaxone-naïve rats. For chronic experiments, rats injected with ceftriaxone or saline for 8 days were also injected with amphetamine or saline on days 6-8 and then challenged with amphetamine 5 days later. Amphetamine produced greater ambulatory and stereotypical activity in amphetamine-pretreated rats than in rats previously naïve to amphetamine. Amphetamine challenge produced less ambulatory and stereotypical activity in rats pretreated with a combination of ceftriaxone (200mg/kg) and amphetamine than in rats pretreated with only amphetamine., Conclusion: The present demonstration that ceftriaxone attenuates amphetamine-induced hyperactivity and behavioral sensitization suggests its documented efficacy against adverse cocaine and morphine effects extends to amphetamine., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Behavioral sensitization in rodents is hypothesized to reflect neuronal adaptations that are related to drug addiction in humans. We evaluated the effects of group exposure on the acute hyperlocomotion and behavioral sensitization induced by four drugs of abuse in C57BL/6 mice: methylenedioxymethamphetamine (MDMA), d-amphetamine, morphine and ethanol., Methods: In the priming session, animals received an ip injection of one of the drugs of abuse and were exposed to an open field either individually or in groups of four. Seven days later, we assessed behavioral sensitization in the challenge session. All animals received an ip injection of the same drug and were exposed to the open field in the same social conditions described for the priming session. Locomotion and social interaction were quantified during each session., Results: Acute MDMA, morphine and ethanol, but not d-amphetamine, increased social interaction. However, group exposure only potentiated MDMA-induced hyperlocomotion. After a challenge injection of each drug, there was no sensitization to the facilitating effect of MDMA, morphine or ethanol on social interaction, but locomotion sensitization developed to all drugs of abuse except ethanol. This sensitization was potentiated by group exposure in MDMA-treated animals, attenuated in morphine-treated animals and not modified in d-amphetamine-treated animals. Acute MDMA enhanced body contact and peaceful following, while acute morphine and ethanol increased social sniffing., Conclusions: These results provide preclinical evidence showing that while different drugs of abuse affect different components of social interaction, the neuronal adaptations related to drug dependence can be critically and specifically influenced by group exposure., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Repeated unavoidable stress induces in rats decreased reactivity to avoidable stressors and an anhedonia-like condition that are reverted by long-term antidepressant treatments and regarded as models of core symptoms of depression. Morphine-sensitized rats present resilience to stress-induced behavioral deficits and, if hyporeactivity to stress models a depressive symptom, stress resistance can be regarded as a manic symptom. This hypothesis is supported by the observation that long-term lithium administration reinstates sensitivity to stress in sensitized rats. The first aim of the study was to examine the effects of carbamazepine, a standard antimanic treatment, on the stress resilience of sensitized rats, to further characterize morphine sensitization as a model of manic symptom. Carbamazepine administration abolished stress resilience but did not interfere with the expression of sensitization. The second aim of the study was to assess whether repeated carbamazepine treatment affected the dopaminergic and behavioral responses to a natural reward, a palatable food (vanilla sugar, VS), in non food-deprived sensitized and control rats and compare these possible effects with those of repeated lithium administration. Control and sensitized rats showed increased extraneuronal dopamine levels in the nucleus accumbens shell after VS consumption and competence to acquire an instrumental VS-sustained appetitive behavior (VAB). Repeated carbamazepine treatment abolished the dopaminergic response to VS consumption and disrupted the competence to acquire VAB in control rats. Lithium-treated rats showed a dopaminergic response to VS and easily acquired the appetitive behavior. In sensitized rats, neither carbamazepine nor lithium administration interfered with the dopaminergic response to VS and the acquisition of VAB. In summary, the effect of carbamazepine on the stress resilience of sensitized rats further supported the hypothesis that morphine sensitization might model some symptoms of mania. Moreover, in control rats carbamazepine treatment elicited an anhedonia-like condition that clearly distinguished the effects of this drug from those of lithium., (Copyright © 2011 Elsevier Inc. All rights reserved.)