Stress is implicated in diverse psychiatric disorders including substance abuse. The locus coeruleus-norepinephrine (LC-NE) system is a major stress response system that is also a point of intersection between stress neuromediators and endogenous opioids and so may be a site at which stress can influence drug-taking behaviors. As social stress is a common stressor for humans, this study characterized the enduring impact of repeated social stress on LC neuronal activity. Rats were exposed to five daily consecutive sessions of social stress using the resident-intruder model or control manipulation. LC discharge rate recorded 2 days after the last manipulation was decreased in stressed rats compared with controls. By 10 days after the last manipulation, LC rates were comparable between groups. Systemic administration of the opiate antagonist, naloxone, robustly increased LC discharge rate in a manner suggestive of opiate withdrawal, selectively in stressed rats when administered 2 or 10 days after the last manipulation. This was accompanied by behavioral signs of mild opiate withdrawal. Western blot and electron microscopic studies indicated that repeated social stress decreased corticotropin-releasing factor type 1 receptor and increased m-opioid receptor levels in the LC. Together, the results suggest that repeated social stress engages endogenous opioid modulation of LC activity and induces signs of cellular and physical opiate dependence that endure after the stress. These cellular effects may predispose individuals with a history of repeated social stress to substance abuse behaviors.

The mechanisms and sites of action of epibatidine-induced antinociception and side effects are poorly understood. The present study tested the hypothesis that the serotonergic dorsal raphe nucleus is a site of action of epibatidine. Behavioral responses of rats to hindpaw formalin injection were compared after direct administration of epibatidine into the dorsal raphe and after subcutaneous administration. Different groups of rats were injected with formalin into the rear paw after administration of either epibatidine (0.01, 0.015, 0.03, and 0.06 g) in the dorsal raphe or epibatidine (2.5-5 g/kg) subcutaneously. Assessment of pain related behavior was done evaluating the incidence of favoring, lifting, and licking of the injected paw in the different groups. Abnormal behavior (freezing) was also recorded. Epibatidine was at least 100 times more potent when administered into the dorsal raphe nucleus versus systemically, implicating this nucleus as a site of action of the analgesic effects of epibatidine. Thus, epibatidine (0.015, 0.03, and 0.06 g) in the dorsal raphe resulted in a significant lower pain score in the second phase of the formalin test compared with control rats and was as effective as subcutaneous epibatidine. The analgesic effects of epibatidine were regionally selective in that administration of epibatidine within the periaqueductal gray area but outside the dorsal raphe area was not analgesic. The highest doses of intraraphe epibatidine (i.e., 0.03-0.06 g) also produced "freezing" behavior immediately after injection, which was relatively short-lived compared with the analgesic effect. Together, the results implicate the dorsal raphe nucleus as a target for the analgesic and perhaps anxiogenic effects of epibatidine.Nicotine and nicotinic agonists have been known for many years to have analgesic properties. However, the high incidence and severity of side effects associated with these drugs has limited their clinical use. Recent studies on the analgesic effects of epibatidine, a nicotinic acetylcholine receptor (nAChR) ligand (Qian et al., 1993;Sullivan et al., 1994;Bannon et al., 1998), and other epibatidine derivatives such as ABT-594 (Bannon et al., 1998) have triggered a new interest on the mechanism of antinociception produced by nicotinic agonists. It has been postulated that nicotinic acetylcholine receptor agonists produce their antinociceptive effects predominantly via activation of descending inhibitory pain pathways originating in the brainstem regions, including the nucleus raphe magnus .Central modulation of pain involves both the nucleus raphe magnus (NRM) and dorsal raphe (DR) nucleus. The NRM can directly control pain transmission in the dorsal horn of the spinal cord via descending projections. The effects of the DR on the spinal cord are most likely mediated by its interconnection with the NRM (Wang and Nakai, 1994). Although there is clear experimental evidence that the NRM mediates the antinociception produced by epibatidine and the nicotinic agonist ABT-594 (Bitner e...

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The parabrachial nucleus (PBN) is an area of the brain stem that controls eating and contains endogenous opioids and their receptors. Previously, we demonstrated that acute activation of µ opioid receptors (MOPR) in the lateral PBN increased food consumption. MOPR's have been divided operationally into µ 1 and µ 2 receptor subtypes on the basis of the ability of naloxonazine (Nlxz) to block the former but not the latter. We used autoradiography to measure whether Nlxz blocks stimulation by the µ 1 /µ 2 agonist DAMGO (D-Ala2, N-Me-Phe4, Gly5-ol-enkephalin) of the incorporation of [ 35 S]-guanosine 5'(γ-thio)triphosphate ([ 35 S]-GTPγS) into sections of the PBN. In vitro, Nlxz dose dependently inhibited receptor coupling in all areas of the PBN. The 1µM concentration of Nlxz reduced stimulation by 93.1±5% in the lateral inferior PBN (LPBNi) and by 90.5±4% in the medial parabrachial subregion (MPBN). Administration of Nlxz directly into the LPBNi decreased both food intake and agonist stimulated coupling, ex vivo, for the 24h period after infusion. Infusion of Nlxz into the intended area reduced food intake by 42.3% below baseline values. Nlxz infusion prevented DAMGO stimulation of G-protein coupling in LPBNi and markedly reduced this stimulation in the MPBN. The incomplete inhibition of DAMGO stimulated coupling in the MPBN is most likely due to the limited diffusion of Nlxz from the site of infusion (LPBNi) into this brain region. In conclusion, this study demonstrates that the µ 1 opioid receptor subtype is present in the parabrachial nucleus of the pons and that these receptors serve to modulate feeding in rats.

Stress is implicated in psychopathology characterized by cognitive dysfunction. Cognitive responses to stress are regulated by the locus coeruleus-norepinephrine (LC-NE) system. As social stress is a prevalent human stressor, this study determined the impact of repeated social stress on the relationship between LC neuronal activity and behavior during the performance of cognitive tasks. Social stress-exposed rats performed better at intradimensional set shifting (IDS) and made fewer perseverative errors during reversal learning (REV). LC neurons of control rats were task responsive, being activated after the choice and before reward. Social stress shifted LC neuronal activity from being task responsive to being reward responsive during IDS and REV. LC neurons of stressed rats were activated by reward and tonically inhibited by reward omission with incorrect choices. In contrast, LC neurons of stress-naive rats were only tonically inhibited by reward omission. Reward-related LC activation in stressed rats was unrelated to predictability because it did not habituate as learning progressed. The findings suggest that social stress history increases reward salience and impairs processes that compute predictability for LC neurons. These effects of social stress on LC neuronal activity could facilitate learning as indicated by improved performance in stressed rats. However, the ability of social stress history to enhance responses to behavioral outcomes may have a role in the association between stress and addictive behaviors. In addition, magnified fluctuations in LC activity in response to opposing behavioral consequences may underlie volatile changes in emotional arousal that characterize post-traumatic stress disorder.