Nociceptive stimuli activate the hypothalamus-habenula circuit to inhibit the mesolimbic reward system

Nociceptive signals interact with various regions of the brain, including those involved in physical sensation, reward, cognition, and emotion. Emerging evidence points to a role of nociception in the modulation of the mesolimbic reward system. The mechanism by which nociception affects dopamine (DA) signaling and reward is unclear. The lateral hypothalamus (LH) and the lateral habenula (LHb) receive somatosensory inputs and are structurally connected with the mesolimbic DA system. Here we show that the LH-LHb pathway is necessary for nociceptive modulation of this system. Our extracellular single-unit recordings and head-mounted microendoscopic calcium imaging revealed that nociceptive stimulation by tail-pinch excited LHb and LH neurons, which was inhibited by chemical lesion of the LH. Tail-pinch decreased extracellular DA release in the nucleus accumbens ventrolateral shell, which was blocked by disruption of the LH. Furthermore, tail-pinch attenuated cocaine-induced locomotor activity, 50-kHz ultrasonic vocalizations and reinstatement of cocaine-seeking behavior, which was inhibited by chemogenetic silencing of the LH-LHb pathway. Our findings suggest that nociceptive stimulation recruits the LH-LHb pathway to inhibit mesolimbic DA system and drug reinstatement.

S77. ROLE OF DOPAMINE AND GLUTAMATE TRANSPORTERS IN GENERATION OF ANTIPSYCHOTIC EFFICACY

Background Antipsychotic drugs are the first line intervention to treat psychosis in schizophrenia and D2 receptor blockade is thought to be their primary mechanism of action. However, multiple lines of evidence from human and animal studies show that D2 receptor blockade is not always correlated with markers of antipsychotic efficacy. We previously demonstrated that reduced antipsychotic efficacy occurs after chronic antipsychotic administration in rodents despite stable D2 blockade, examined using PET imaging. Instead, we found that changes in expression of the dopamine transporter (DAT) were associated with decreases in endogenous dopamine and dopamine-mediated autoinhibition. These studies have led us to examine the DAT as a critical player in generation of an antipsychotic response. Methods Using antisense morpholino oligonucleotides, administered for 3 consecutive days using Long Evans rats, we selectively blocked translation of DAT or GLT-1 mRNA in the core of the nucleus accumbens, a brain region critical for motor outputs in response to salient stimuli. Baseline locomotion was monitored prior to and after an acute i.p. injection of haloperidol. Next, locomotion was monitored in response to a tail pinch or acute i.p. administration of cocaine. Transporter expression was quantified during acute or chronic haloperidol treatment using confocal microscopy. Results We found that DAT knockdown enhanced tail pinch-induced locomotion after acute haloperidol administration. Additionally, knockdown of the glutamate transporter GLT-1 strongly enhanced locomotion induced by tail pinch or cocaine injection after antipsychotic treatment. Confocal analysis of GLT-1 expression after acute or chronic haloperidol revealed significant GLT-1 up-regulation during a time period associated with antipsychotic efficacy. Discussion Our findings demonstrate a cause/effect relationship between reduced DAT and the behavioral response to an acute injection of antipsychotics in rodents. In all, our data point to the importance of both dopamine and glutamate uptake in the efficacy of antipsychotic drugs and argue against a D2-centric hypothesis of antipsychotic action.

Screening of N-Benzoyl Isoserine Methyl Ester (N-bime) for anti-inflammatory analgesic activity and toxicity profile in animals

Background: Pain and inflammation are the basic processes involved in the pathogenesis of many diseases. Non-steroidal anti-inflammatory drugs are often used to treat rheumatic diseases. The study compound N-Benzoyl Isoserine Methyl Ester (N-bime) is a newly synthesized propionic acid derivative by National Chemical Laboratory, Pune. Since the biological data of this compound is not available, the present study has been planned to screen this compound for anti-inflammatory, analgesic activity and its toxicity profile in animals.Methods: Single dose toxicity study was carried out in rats. Anti-inflammatory activity was tested by Rat Hind Paw Oedema and Cotton Pellet Implantation method. For Analgesic activity, Acetic acid induced writhing and Tail Pinch method was used. Yeast induced Pyrexia was used for evaluation of anti-pyretic activity. Ibuprofen was the positive control. Data are presented as mean±SEM. Statistical analysis was performed by analysis of variance and students unpaired‘t’ test.Results: The test compound N-bime did not show any apparent adverse effects or mortality in the dose range 1mg - 500mg / 100gm body weight in animals. It showed better anti-inflammatory actions in higher doses as compared to Ibuprofen (p˂ 0.05). In acetic acid induced writhing test N-bime offered better protection against writhes, than Ibuprofen. But, both failed to demonstrate analgesic activity in the Tail Pinch method. N-bime showed a gradual decrease in temperature in the anti-pyretic test (P<0.001).Conclusions: The present study indicates that N-bime does possess anti-inflammatory, analgesic and weak anti-pyretic properties like the NSAIDs. It has proved to be safe in the dose range of 1mg - 500mg / 100gm body weight in rats and mice.

A comparative study for antinociceptive potential of vitamin D3 with diclofenac in animal models

Background: Calcitriol is one of the active forms of vitamin D. It not only acts on calcium metabolism but might have a role in treating various disorders also through vitamin D receptors that are present in many tissues besides intestine and bone. This study was conducted to compare antinociceptive activity of Calcitriol with Diclofenac and Morphine in animal models.Methods: In this study, healthy Swiss albino mice were taken after permission from IAEC. Mice were divided into six groups as one control- treated with normal saline, two standards - treated with diclofenac and treated with morphine while three tests - treated with Calcitriol in dose of 15µg /kg/mice, 30µg/kg/mice and 60µg/kg/mice respectively. Comparison of antinociception was done using Tail pinch and writhing method.Results: Tail pinch and Writhing methods were used for comparison of antinociceptive activity. In tail pinch model, Calcitriol showed some analgesia at 30 and 60μg/Kg doses, which was more than control but not comparable with the standard Morphine. In writhing method, test doses of Calcitriol (15 and 30μg/Kg) failed to show analgesic efficacy in inflammatory pain but test dose of 60μg/Kg showed some analgesic activity which was not comparable with standard Diclofenac.Conclusions: Antinociception was exhibited at higher doses of Calcitriol by tail pinch method while in writhing method analgesic activity was shown with only 60 μg/Kg dose of Calcitriol. The results obtained from this study needs to be further evaluated by planning extensive animal experimentation.

Orexigenic response to tail pinch: role of brain NPY1 and corticotropin releasing factor receptors

Tail pinch stimulates food intake in rats. We investigated brain mechanisms of this response and the influence of repeated exposure. Sprague-Dawley rats received acute (5 min) or repeated (5 min/day for 14 days) tail pinch using a padded clip. Acute tail pinch increased 5-min food intake compared with control (0.92 ± 0.2 vs. 0.03 ± 0.01 g, P < 0.01). This response was inhibited by 76% by intracerebroventricular injection of BIBP-3226, a neuropeptide Y1 (NPY1) receptor antagonist, increased by 48% by astressin-B, a corticotropin-releasing factor (CRF) receptor antagonist, and not modified by S-406-028, a somatostatin subtype 2 antagonist. After the 5-min tail pinch without food, blood glucose rose by 21% ( P < 0.01) while changes in plasma acyl ghrelin (+41%) and adrenocorticotropic hormone (+37%) were not significant. Two tail pinches (45 min apart) activate pontine and hindbrain catecholaminergic and hypothalamic paraventricular CRF neurons. After 14 days of repeated tail pinch, the 5-min orexigenic response was not significantly different from days 2 to 11 but reduced by 50% thereafter ( P < 0.001). Simultaneously, the 5-min fecal pellet output increased during the last 5 days compared with the first 5 days (+58%, P < 0.05). At day 14, the body weight gain was reduced by 22%, with a 99% inhibition of fat gain and a 25% reduction in lean mass ( P < 0.05). The orexigenic response to acute 5-min tail pinch is likely to involve the activation of brain NPY1 signaling, whereas that of CRF tends to dampen the acute response and may contribute to increased defecation and decreased body weight gain induced by repeated tail pinch.