Hypothalamic Neuropeptide S receptor blockade decreases discriminative cue-induced reinstatement of cocaine seeking in the rat

Rationale

Previous studies have shown that activation of brain neuropeptide S receptor (NPSR) facilitates reinstatement of cocaine seeking elicited by environmental cues predictive of drug availability. This finding suggests the possibility that blockade of NPSR receptors may be of therapeutic benefit in cocaine addiction. To evaluate this hypothesis, we investigated the effect of two newly synthetized NPSR antagonists, namely the quinolinone-amide derivative NPSR-QA1 and the NPS peptidic analogue [D-Cys(tBu)⁵]NPS on cocaine self-administration and on discriminative cue-induced relapse to cocaine seeking in the rat.

Methods

Separate groups of rats self-administered food and cocaine 0.25 mg/kg/inf in FR1 and FR5 (fixed ratio reinforcement schedules) for 30-min and 2-h sessions per day. After food and cocaine intake reached baseline levels, the effect of NPSR-QA1 was tested on cocaine and food self-administration. The NPSR-QA1 was injected intraperitoneally and its effect on discriminative cue-induced reinstatement was evaluated, while [D-Cys(tBut)⁵]NPS was injected intracranially, intra-lateral hypothalamus, intra-perifornical area of the hypothalamus, and intra-central amygdala. The effect of the NPSR-QA1 on extinction of cocaine seeking was also assessed.

Results

Intraperitoneal administration of NPSR-QA1 (15–30 mg/kg) did not affect cocaine self-administration. Conversely, NPSR-QA1 (15–30 mg/kg) decreased discriminative cue-induced cocaine relapse. At the lowest dose, this effect was specific, while at the highest dose, NPSR-QA1 also reduced food self-administration. The efficacy of NPSR antagonism on cocaine seeking was confirmed with [D-Cys(tBu)⁵]NPS (10–30 nmol/rat) as it markedly inhibited relapse behavior following site-specific injection into the lateral hypothalamus and the perifornical area of the hypothalamus but not into the central amygdala.

Conclusions

The identification of the NPS/NPSR system as an important new element involved in the physiopathology of cocaine addiction and the discovery of the anti-addictive properties of NPSR antagonists opens the possibility of exploring a new mechanism for cocaine addiction treatment.     

Pregabalin reduces alcohol drinking and relapse to alcohol seeking in the rat

Rationale  

Pregabalin (Lyrica™) is a structural analogue of γ-aminobutyric acid (GABA) approved by FDA for partial epilepsy, neuropathic pain and recently generalized anxiety disorder. While the exact cellular mechanism of action of pregabalin is still unclear, evidence from several studies suggests that it reduces excitatory neurotransmitter release and postsynaptic excitability.     

PPARγ Activation Attenuates Opioid Consumption and Modulates Mesolimbic Dopamine Transmission

PPARγ is one of the three isoforms identified for the peroxisome proliferator-activated receptors (PPARs) and is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. PPARγ has been long studied for its role in adipogenesis and glucose metabolism, but the discovery of the localization in ventral tegmental area (VTA) neurons opens new vistas for a potential role in the regulation of reward processing and motivated behavior in drug addiction. Here, we demonstrate that activation of PPARγ by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. These effects are associated with a marked reduction of heroin-induced increase in phosphorylation of DARPP-32 protein in the nucleus accumbens (NAc) and with a marked and selective reduction of acute heroin-induced elevation of extracellular dopamine (DA) levels in the NAc shell, as measured by in vivo microdialysis. Through ex vivo electrophysiology in acute midbrain slices, we also show that stimulation of PPARγ attenuates opioid-induced excitation of VTA DA neurons via reduction of presynaptic GABA release from the rostromedial tegmental nucleus (RMTg). Consistent with this finding, site-specific microinjection of pioglitazone into the RMTg but not into the VTA reduced heroin taking. Our data illustrate that activation of PPARγ may represent a new pharmacotherapeutic option for the treatment of opioid addiction.     

Effect of an Exercise Programme for the Prevention of Back and Neck Pain in Poultry Slaughterhouse Workers

The objectives of this study were to determine the effectiveness of a programme of prevention exercises conducted in a corporate environment in poultry industry slaughterers suffering from musculoskeletal disorders. Forty workers, 70% female (mean ± SD age: 44.4 ± 8.4 years) were consecutively, in an alternative way, assigned to one of two groups receiving either set of 10 sessions (experimental or control group). The experimental group followed an exercise programme for a period of five weeks and a protocol of home exercises. The control group performed the exercise protocol only at home. The Roland Morris Disability Questionnaire (RMDQ) and the Oswestry Disability Index (ODI) to measure disability, the Visual Analogue Scale (VAS) score and the Pain Drawing to measure pain were used as outcome evaluations. A significant effect of time interaction (all P <0.001 and; F = 40.673; F = 33.907 and F = 25.447) existed for lumbar VAS, RMDQ and ODI immediately after the intervention (all P < 0.006). No significant group effect or group‐by‐time interaction was detected for any of them, which suggests that both groups improved in the same way. This study shows that a programme of prevention exercises may have a positive effect in improving musculoskeletal disorders of slaughterhouse workers. Pain decreased in the lumbar region, and there was an almost significant reduction in disability. Copyright © 2014 John Wiley & Sons, Ltd.     

Analgesic tolerance to morphine is regulated by PPARγ

Background and Purpose

Opioid drugs are potent analgesics. However, their chronic use leads to the rapid development of tolerance to their analgesic effects and subsequent increase of significant side effects, including drug dependence and addiction. Here, we investigated the role of PPARγ in the development of analgesic tolerance to morphine in mice.

Experimental Approach

We monitored analgesia on alternate days using the tail immersion test.

Key Results

Daily administration of morphine (30 mg·kg⁻¹, bid) resulted in the rapid development of tolerance to thermal analgesia. Co-administration of pioglitazone (10 and 30 mg·kg⁻¹, bid) significantly attenuated the development and expression of tolerance. However, pretreatment with GW-9662 (5 mg·kg⁻¹, bid), a selective PPARγ antagonist, completely abolished this effect. Injection of GW-9662 and a lower dose of morphine (15 mg·kg⁻¹, bid) accelerated the development of tolerance to its antinociceptive effect. Subsequently, we found that conditional neuronal PPARγ knockout (KO) mice develop a more rapid and pronounced tolerance to morphine antinociception compared with wild-type (WT) controls. Moreover, in PPARγ KO mice, pioglitazone was no longer able to prevent the development of morphine tolerance.

Conclusions and Implications

Overall, our results demonstrate that PPARγ plays a tonic role in the modulation of morphine tolerance, and its pharmacological activation may help to reduce its development. These findings provide new information about the role of neuronal PPARγ and suggest that combining PPARγ agonists with opioid analgesics may reduce the development of tolerance and possibly attenuate the potential for opioid abuse.Table of Links