Behavioural Pharmacology最新文献

Stress and pain are interleaved at numerous levels - influencing each other. Stress can increase the nociception threshold in animals, long-known as stress-induced analgesia (SIA). Orexin is known as a neuropeptide that modulates pain. The effect of stress on the mesolimbic system in the modulation of pain is known. The role of the intra-accumbal orexin receptors in the modulation of acute pain by forced swim stress (FSS) is unclear. In this study, 117 adult male albino Wistar rats (270-300 g) were used. The animals were unilaterally implanted with cannulae above the NAc. The antagonist of the orexin-1 receptor (OX1r), SB334867, and antagonist of the orexin-2 receptor (OX2r), TCS OX2 29, were microinjected into the NAc in different doses (1, 3, 10, and 30 nmol/0.5 µl DMSO) before exposure to FSS for a 6-min period. The tail-flick test was carried out as an assay nociception of acute pain, and the nociceptive threshold [tail-flick latency (TFL)] was measured for 60-minute. The findings demonstrated that exposure to acute stress could remarkably increase the TFLs and antinociceptive responses. Moreover, intra-accumbal microinjection of SB334867 or TCS OX2 29 blocked the antinociceptive effect of stress in the tail-flick test. The contribution of orexin receptors was almost equally modulating SIA. The present study's findings suggest that OX1r and OX2r within the NAc modulate stress-induced antinociceptive responses. The intra-accumbal microinjection of orexin receptors antagonists declares inducing antinociceptive responses by FSS in acute pain. Proposedly, intra-accumbla orexinergic receptors have a role in the development of SIA.

The nicotine acetylcholinergic receptor (nAchR) in the central nucleus of the amygdala (CeA) is known to modulate anxiety traits as well as ethanol-induced behavioral effects. Therefore, the present study investigated the role of CeA nAChR in the tolerance to ethanol anxiolysis and withdrawal-induced anxiety-related effects in rats on elevated plus maze (EPM). To develop ethanol dependence, rats were given free access to an ethanol-containing liquid diet for 10 days. To assess the development of tolerance, separate groups of rats were challenged with ethanol (2 g/kg, i.p.) on days 1, 3, 5, 7 and 10 during the period of ethanol exposure, followed by an EPM assessment. Moreover, expression of ethanol withdrawal was induced after switching ethanol-dependent rats to a liquid diet on day 11, and withdrawal-induced anxiety-like behavior was noted at different post-withdrawal time points using the EPM test. The ethanol-dependent rats were pretreated with intra-CeA (i.CeA) (bilateral) injections of nicotine (0.25 µg/rat) or mecamylamine (MEC) (5 ng/rat) before the challenge dose of ethanol on subthreshold tolerance on the 5th day or on peak tolerance day, that is, 7th or 10th, and before assessment of postwithdrawal anxiety on the 11th day on EPM. Bilateral i.CeA preadministration of nicotine before the challenge dose of ethanol on days 5, 7 and 10 exhibited enhanced tolerance, while injection of MEC, completely mitigated the tolerance to the ethanol-induced antianxiety effect. On the other hand, ethanol-withdrawn rats pretreated i.CeA with nicotine exacerbated while pretreatment with MEC, alleviated the ethanol withdrawal-induced anxiety on all time points. Thus, the present investigation indicates that stimulation of nAChR in CeA negatively modulates the ethanol-induced chronic behavioral effects on anxiety in rats. It is proposed that nAChR antagonists might be useful in the treatment of alcohol use disorder and ethanol withdrawal-related anxiety-like behavior.

It has been demonstrated that the nucleus accumbens (NAc) plays an important role in modulation of nociception due to its extensive connections with different regions of the brain. In addition, this nucleus receives histaminergic projections from tuberomammillary nucleus. Considering the role of the central histaminergic system in nociception, the effect of histamine and its H 2 and H 3 receptors agonist and antagonist microinjections into the NAc on orofacial formalin nociception was investigated. In male Wistar rats, using stereotaxic surgery, two guide cannulas were bilaterally implanted into the right and left sides of the NAc. Diluted formalin solution (1.5%, 50 µl) injection into the vibrissa pad led to orofacial nociception. Immediately after injection, face rubbing was observed at 3-min blocks for 45 min. Orofacial formalin nociception was characterized by a biphasic nociceptive response (first phase: 0-3 min and second phase: 15-33 min). Microinjections of histamine (0.5 and 1 μg/site), dimaprit (1 μg/site, H 2 receptor agonist) and thioperamide (2 μg/site, H 3 receptor antagonist) attenuated both phases of formalin orofacial nociception. Prior microinjection of famotidine (2 μg/site) inhibited the antinociceptive effects of dimaprit (1 μg/site). Furthermore, comicroinjection of thioperamide (2 μg/site) and immepip (1 μg/site) prevented thioperamide (2 μg/site)-induced antinociception. Naloxone (2 μg/site) also prevented histamine, dimaprit- and thioperamide-induced antinociception. The results of this study demonstrate that at the level of the NAc, histamine and its H 2 and H 3 receptors are probably involved in the modulation of orofacial nociception with an opioid system-dependent mechanism.

Remarkable performance improvements occur at the end of the third postnatal week in rodents tested in various tasks that require navigation according to spatial context. While alterations in hippocampal function at least partially subserve this cognitive advancement, physiological explanations remain incomplete. Previously, we discovered that developmental modifications to hippocampal glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in juvenile rats was related to more mature spontaneous alternation behavior in a symmetrical Y-maze. Moreover, a positive allosteric modulator of AMPA receptors enabled immature rats to alternate at rates seen in older animals, suggesting an excitatory synaptic limitation to hippocampal maturation. We then validated the Barnes maze for juvenile rats in order to test the effects of positive AMPA receptor modulation on a goal-directed spatial memory task. Here we report the effects of the AMPA receptor modulator, CX614, on spatial learning and memory in the Barnes maze. Similar to our prior report, animals just over 3 weeks of age display substantial improvements in learning and memory performance parameters compared to animals just under 3 weeks of age. A moderate dose of CX614 enabled immature animals to move more directly to the goal location, but only after 1 day of training. This performance improvement was observed on the second day of training with drug delivery or during a memory probe trial performed without drug delivery after the second day of training. Higher doses created more search errors, especially in more mature animals. Overall, CX614 provided modest performance benefits for immature rats in a goal-directed spatial memory task.

We hypothesized that opioid receptor antagonists would inhibit motivated behavior produced by a natural reward. To evaluate motivated responses to a natural reward, mice were given access to running wheels for 71.5 h in a multi-configuration testing apparatus. In addition to a running wheel activity, locomotor activity (outside of the wheel), food and water intake, and access to a food container were measured in the apparatus. Mice were also tested separately for novel-object exploration to investigate whether naloxone affects behavior unrelated to natural reward. In untreated mice wheel running increased from day 1 to day 3. The selective µ-opioid receptor antagonist β-funaltrexamine (β-FNA) (5 mg/kg) slightly decreased wheel running, but did not affect the increase in wheel running from day 1 to day 3. The non-selective opioid receptor antagonist naloxone produced a greater reduction in wheel running than β-FNA and eliminated the increase in wheel running that occurred over time in the other groups. Analysis of food access, locomotor behavior, and behavior in the novel-object test suggested that the reduction in wheel running was selective for this highly reinforcing behavior. These results indicate that opioid receptor antagonism reduces responses to the natural rewarding effects of wheel running and that these effects involve multiple opioid receptors since the non-selective opioid receptor antagonist had greater effects than the selective µ-opioid receptor antagonist. It is possible that at the doses employed, other receptor systems than opioid receptors might be involved, at least in part, in the effect of naloxone and β-FNA.

We investigated the effects of histamine and GABA A receptor agents on pain and depression-like behaviors and their interaction using a tail-flick test and the forced swimming test (FST) in male mice. Our data revealed that intraperitoneal administration of muscimol (0.12 and 0.25 mg/kg) increased the percentage of maximum possible effect (%MPE) and area under the curve (AUC) of %MPE, indicating an antinociceptive response. Intraperitoneal injection of bicuculline (0.5 and 1 mg/kg) decreased %MPE and AUC of %MPE, suggesting hyperalgesia. Moreover, muscimol by reducing the immobility time of the FST elicited an antidepressant-like response but bicuculline by enhancing the immobility time of the FST caused a depressant-like response. Intracerebroventricular (i.c.v.) microinjection of histamine (5 µg/mouse) enhanced %MPE and AUC of %MPE. i.c.v. infusion of histamine (2.5 and 5 µg/mouse) decreased immobility time in the FST. Co-administration of different doses of histamine along with a sub-threshold dose of muscimol potentiated antinociceptive and antidepressant-like responses produced by histamine. Cotreatment of different doses of histamine plus a noneffective dose of bicuculline reversed antinociception and antidepressant-like effects elicited by histamine. Cotreatment of histamine, muscimol, and bicuculline reversed antinociceptive and antidepressant-like behaviors induced by the drugs. The results demonstrated additive antinociceptive and antidepressant-like effects between histamine and muscimol in mice. In conclusion, our results indicated an interaction between the histaminergic and GABAergic systems in the modulation of pain and depression-like behaviors.

Stress-induced antinociception (SIA) is due to the activation of several neural pathways and neurotransmitters that often suppress pain perception. Studies have shown that the orexin neuropeptide system is essential in pain modulation. Therefore, this study aimed to investigate the role of orexinergic receptors in the hippocampal CA1 region in modulating SIA response during the formalin test as an animal model of inflammatory pain. The orexin-1 receptor (OX1r) antagonist, SB334867, at 1, 3, 10, and 30 nmol or TCS OX2 29 as an orexin-2 receptor (OX2r) antagonist at the same doses were microinjected into the CA1 region in rats. Five minutes later, rats were exposed to restraint stress (RS) for 3 h, and pain-related behaviors were monitored in 5-min blocks for the 60-min test period in the formalin test. Results showed that applying RS for 3 h reduced pain responses in the early and late phases of the formalin test. The main findings showed that intra-CA1 injection of orexin receptor antagonists reduced the antinociception caused by stress in both phases of the formalin test. In addition, the contribution of OX2r in mediating the antinociceptive effect of stress was more prominent than that of OX1r in the early phase of the formalin test. However, in the late phase, both receptors worked similarly. Accordingly, the orexin system and its two receptors in the CA1 region of the hippocampus regulate SIA response to this animal model of pain in formalin test.