sb-334867-a and Morphine-Dependence

In this study, we investigated the effect of long-term administration of orexin receptor 1 (OXR1) antagonist on naloxone-precipitated morphine withdrawal symptoms and nociceptive behaviors in morphine-dependent rats.. Wistar rats received subcutaneous (s.c.) injections of morphine (6, 16, 26, 36, 46, 56, and 66 mg/kg, 2 ml/kg) at an interval of 24 h for 7 days. In chronic groups, the OXR1 antagonist, SB-334867 (20 mg/kg, i.p.), or its vehicle, was injected repetitively from postnatal day 1 (PND1)-PND23 and then for the following seven days before each morphine injection. Meanwhile, in acute groups, SB-334867, or its vehicle, was administered before each morphine injection. In groups of rats that were designated for withdrawal experiments, naloxone (2.5 mg/kg, i.p.) was administered after the last injection of morphine. In the formalin-induced pain, the effect of OXR1 inhibition on the antinociceptive effects of morphine was measured by injecting formalin after the final morphine injection.. Animals that received long-term SB-334867 administration before morphine injection demonstrated a significant reduction in chewing, defecation, diarrhea, grooming, teeth chattering, wet-dog shake, and writhing. Inhibiting OXR1 for a long time increased formalin-induced nociceptive behaviors in interphase and phase II of the formalin-induced pain.. Our results indicated that the inhibition of OXR1 significantly reduces the development of morphine dependence and behavioral signs elicited by the administration of naloxone in morphine-dependent rats. Furthermore, the prolonged blockade of OXR1 might be involved in formalin-induced nociceptive behaviors.

Topics: Animals; Behavior, Animal; Benzoxazoles; Disease Models, Animal; Morphine; Morphine Dependence; Naloxone; Naphthyridines; Narcotic Antagonists; Narcotics; Nociceptive Pain; Orexin Receptor Antagonists; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Urea

Orexin neuropeptides are implicated in the expression of morphine dependence. Locus coeruleus (LC) nucleus is an important brain area involving in the development of withdrawal signs of morphine and contains high expression of orexin type 1 receptors (OX1Rs). Despite extensive considerations, effects of immediate inhibition of OX1Rs by a single dose administration of SB-334867 prior to the naloxone-induced activation of LC neurons remains unknown. Therefore, we examined the direct effects of OX1Rs acute blockade on the neuronal activity of the morphine-dependent rats which underwent naloxone administration. Adult male rats underwent subcutaneous administration of 10 mg/kg morphine (two times/day) for a ten-day period. On the last day of experiment, intra-cerebroventricular administration of 10 μg/μl antagonist of OX1Rs, SB-334867, was performed just before intra-peritoneal injection of 2 mg/kg naloxone. Thereafter, in vivo extracellular single unit recording was employed to evaluate the electrical activity of LC neuronal cells. The outcomes demonstrated that morphine tolerance developed following ten-day of injection. Then, naloxone administration causes hyperactivity of LC neuronal cells, whereas a single dose administration of SB-334867 prior to naloxone prevented the enhanced activity of neurons upon morphine withdrawal. Our findings indicate that increased response of LC neuronal cells to applied naloxone could be prevented by the acute inhibition of the OX1Rs just before the naloxone treatment.

Topics: Action Potentials; Analgesics, Opioid; Animals; Benzoxazoles; Injections, Intraperitoneal; Injections, Intraventricular; Locus Coeruleus; Male; Morphine; Morphine Dependence; Naloxone; Naphthyridines; Narcotic Antagonists; Neurons; Orexin Receptor Antagonists; Orexin Receptors; Rats; Rats, Wistar; Urea

Self-control problems are a typical character of drug addiction and excessive food consumption and it has been shown that natural rewards and drugs of abuse share parts of the same neural substrate and reward processing in the brain. Different brain areas are involved in natural and drug reward processing including the mesolimbic pathway, amygdala, nucleus accumbens (NAc), and prefrontal cortex. Considering the important role of orexins in the addictive behavior and the presence of orexin-1 subtype receptors (Orx1R) in the medial prefrontal cortex (mPFC), this study investigated the role of mPFC in natural- and drug-reward seeking behaviors to deepen our understanding of possible similarities or differences. To induce food- or morphine-conditioned place preference (CPP), adult male Wistar rats underwent CPP testing and received intra-mPFC doses of SB334867 (3, 10, or 30 nM/0.5 μl DMSO 12%), as an Orx1R antagonist, during the acquisition or expression phases of the CPP test. Results indicated that microinjection of Orx1R antagonist into the mPFC had similar effects on both morphine- and food-induced CPP and attenuated CPP scores in the acquisition and expression phases of the CPP test. The data demonstrated that Orx1Rs in the mPFC regulate the reward-related effects of morphine- and food-induced reward.

Topics: Animals; Benzoxazoles; Conditioning, Operant; Drug-Seeking Behavior; Food; Male; Morphine; Morphine Dependence; Naphthyridines; Orexin Receptor Antagonists; Orexin Receptors; Prefrontal Cortex; Rats; Rats, Wistar; Reward; Urea

It has been reported that orexins A and B are involved in the mediation of drug reward. In addition, the nucleus accumbens (NAc) has an important role in the development of morphine-conditioned place preference (CPP) and morphine sensitization. In the present study, we aimed to evaluate the role of orexin receptors within the NAc in morphine sensitization using CPP paradigm. Adult male Wistar rats were used and were bilaterally implanted by two cannulae in the NAc. The animals received intra-accumbal administration of OX1 or OX2 receptor antagonists, SB-334867 (0.1, 1, and 10 nM/side) or TCS OX2 29 (2, 10, and 20 nM/side), 10 min before morphine injection during the sensitization period, during which the animals received repeated administration of morphine (5 mg/kg; s.c.) once daily for three days followed by 5 morphine injection-free days. Then the CPP paradigm was conducted for the evaluation of morphine rewarding properties by injecting a sub-threshold dose of morphine (0.5 mg/kg; s.c.). The results showed that bilateral administration of OX1 receptor antagonist into the NAc reduced acquisition of morphine sensitization in a dose-dependent manner, but OX2 receptor antagonist produced similar effect only at its highest dose, indicating that OX1 and OX2 receptors within the NAc are involved in the acquisition of morphine sensitization.

Topics: Animals; Benzoxazoles; Conditioning, Classical; Conditioning, Operant; Conditioning, Psychological; Drug Interactions; Drug Tolerance; Isoquinolines; Male; Morphine; Morphine Dependence; Naphthyridines; Nucleus Accumbens; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Pyridines; Rats; Rats, Wistar; Reward; Urea

Orexin plays a key role in mediating stress-induced drug relapse. However, the role of different types of orexinergic receptors that modulate stress-induced drug seeking remains unknown. The nucleus accumbens (NAc) has an important role in the reward system and receives orexinergic projections of the lateral hypothalamus. In addition, orexin interacts with other receptors that are involved in drug reinstatement. Therefore, in the present study, the role of orexin receptors in the NAc in morphine priming- induced reinstatement and the effect of food deprivation (FD) on drug reinstatement were examined. The extinguished morphine preference rats were tested for reinstatement following the 24-h FD condition after conditioning was induced. In the other groups, the animals were given intra-accumbal administration of SB334867 (01, 1 and 10 nM/0.5 μl DMSO) as an orexin-1 receptor antagonist and TCSOX229 (1, 5 and 25 nM/0.5 μl DMSO), as an orexin-2 receptor antagonist. The results showed that the blockade of two types of orexin receptors in the NAc remarkably attenuated the effect of FD on the drug reinstatement; however, they were more effective in FD condition. These findings indicate that the NAc is a brain area within which orexin has a fundamental role in the effect of stress on morphine-induced reinstatement and the effect of food deprivation- on the reinstatement of morphine.

Topics: Animals; Benzoxazoles; Disease Models, Animal; Dose-Response Relationship, Drug; Drug-Seeking Behavior; Food Deprivation; Isoquinolines; Male; Morphine; Morphine Dependence; Naphthyridines; Narcotics; Nucleus Accumbens; Orexin Receptor Antagonists; Orexin Receptors; Pyridines; Rats, Wistar; Urea

Hippocampus (HIP) is an essential brain site to study reward-related learning tasks, such as conditioning place preference (CPP) that can measure the preference for environmental stimuli related to reward. Furthermore, orexin neurons, situated exclusively in the lateral hypothalamus (LH) and link the rewarding effects of drugs of abuse in the LH and the CA1 region of the HIP. Therefore, in this study adult male rats were conditioned with morphine using a CPP paradigm. After the eighth day of the extinction period, on the reinstatement day, orexin-1 and orexin-2 receptor antagonists were administered bilaterally into the CA1 region prior to acute stress. Using two different types of acute stress, forced swim stress (FSS) and food deprivation (FD), the role of orexin-1 and orexin-2 receptors in the CA1 brain region in FSS and FD induced reinstatement was investigated. Our results showed that application of the orexin-1 and orexin-2 antagonists, SB334867 and TCSOX2 29, respectively, reduced the CPP scores in the reinstatement phase. Moreover, it can be concluded that orexin neurons are activated in acute stress states, such as FSS and FD, as blocking the orexin receptors, decreased the effects of acute stress in triggering the reinstatement of morphine-CPP.

Topics: Animals; Benzoxazoles; CA1 Region, Hippocampal; Drug-Seeking Behavior; Extinction, Psychological; Food Deprivation; Isoquinolines; Male; Morphine Dependence; Naphthyridines; Neurons; Orexin Receptor Antagonists; Orexin Receptors; Pyridines; Rats, Wistar; Stress, Psychological; Swimming; Urea

The aim of this study was to evaluate the effects of orexin type-1 receptor (OX1R) antagonism in locus coeruleus (LC) nucleus on the development of morphine physical dependence in rats. Animals were rendered dependent on morphine by subcutaneous (s.c.) administration of morphine sulfate (6, 16, 26, 36, 46, 56 and 66 mg/kg, 2 ml/kg) at set intervals of 24 h for 7 days. Immediately before each morphine administration, the animals received intra-LC administration of SB-334867 (3 mM, 0.2 μl), a selective orexin type-1 receptor antagonist. On day 8, naloxone (3 mg/kg, i.p.) was injected and physical dependence was evaluated for 30 min. Our results showed that administration of OX1R antagonist before each morphine injection significantly decreased somatic signs of naloxone-induced morphine withdrawal syndrome, including defecation, wet-dog shake, diarrhea, jumping, scratching, and teeth chattering. These results suggest that the activation of OX1R in LC nucleus might be involved in the development of morphine dependency.

Topics: Animals; Benzoxazoles; Locus Coeruleus; Male; Morphine; Morphine Dependence; Naphthyridines; Orexin Receptor Antagonists; Orexin Receptors; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Urea

Conditioned place preference (CPP) has been associated with orexinergic (hypocrtinergic) system activation in naïve mice; however, the distinct role of different receptors of orexin in this paradigm has not been characterized yet. Moreover, the relationship between orexins and morphine in dependent mice may not be equal to naïve mice and seems noteworthy to investigate. We investigated the effects of systemic administration of orexin-1-receptor antagonist, SB 334867, and orexin-2 receptor antagonist, TCS-OX2-29 on the acquisition and expression of morphine conditioned place preference (CPP) in both naïve and morphine-dependent mice. We tested SB 334867 in three doses (10, 20 and 30 mg/kg), TCS-OX2-29 in two doses (5 and 10 mg/kg) and morphine with highest effective dose based on our dose-response experiment (5 mg/kg). Our results revealed that while SB 334867 suppressed CPP acquisition and expression in naïve mice, it failed to block CPP acquisition and expression in morphine dependent animals. In contrast, TCS-OX2-29 suppressed CPP acquisition and expression in both naïve and dependent mice significantly. The rewarding effect of morphine has stronger correlation with orexin-2 receptors in morphine-dependent mice while it depends on both kinds of receptors in naïve mice. This finding, if confirmed in other studies, persuades us to further investigate the role of orexin-2 receptor antagonists as potent drugs in addiction treatment.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Antigens, Surface; Benzoxazoles; Conditioning, Operant; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Isoquinolines; Male; Mice; Morphine; Morphine Dependence; Naphthyridines; Orexin Receptors; Pyridines; Receptors, Cell Surface; Receptors, Neuropeptide; Urea

It has been shown that orexin neuropeptides contribute to morphine-induced physical dependence. The locus coeruleus (LC), which receives a dense extra-hypothalamic orexinergic projection, is a key brain region implicated in the expression of somatic signs of morphine withdrawal syndrome. The aim of the present study is to investigate the role of LC orexin type 1 receptors (OXR1) on naloxone-precipitated morphine withdrawal signs in rats. Adult male Wistar rats were rendered dependent on morphine by subcutaneous (s.c.) injection of morphine sulfate (10mg/kg) at an interval of 12h for 9 days. On day 10, naloxone (1mg/kg i.p.) was injected 2h after morphine administration. Somatic signs of withdrawal were then evaluated in a clear Plexiglas test chamber (30 cm diameter, 50 cm height) for 25 min. One group of animals received intra-LC SB-334867-A, a selective OXR1 antagonist, (100 microM, 0.2 microl) immediately before naloxone. In the control group, SB-334867-A vehicle was microinjected into the LC in the same manner. The results showed that intra-LC OXR1 receptor blockade significantly decreased the somatic signs of withdrawal including chewing, diarrhea, scratching, teeth chattering, wet-dog shake and ptosis. These results suggest that activation of OXR1 in the LC might be involved in the expression of withdrawal signs in morphine dependent rats.

Topics: Animals; Benzoxazoles; Injections, Intraventricular; Locus Coeruleus; Male; Morphine; Morphine Dependence; Naloxone; Naphthyridines; Narcotic Antagonists; Narcotics; Orexin Receptors; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Substance Withdrawal Syndrome; Urea