Explore the vast range of titles available.

Mu opioid receptor agonists are among the most powerful analgesic medications but also among the most addictive. The current opioid crisis has energized a quest to develop opioid analgesics that are devoid of untoward effects. Since their discovery in the 1970’s, there have been major advances in our understanding of the endogenous opioid systems that these drugs target. Yet many questions remain and the development of non-addictive opioid analgesics has not been achieved. However, access to new molecular, genetic and computational tools have begun to elucidate the structural dynamics of opioid receptors, the scaffolding that links them to intracellular signaling cascades, their cellular trafficking and the distinct ways that various opioid drugs modify them. This mini-review highlights some of the chemical and pharmacological findings and new perspectives that have arisen from studies using these tools. They reveal multiple layers of complexity of opioid receptor function, including a spatiotemporal specificity in opioid receptor-induced cellular signaling, ligand-directed biased signaling, allosteric modulation of ligand interactions, heterodimerization of different opioid receptors, and the existence of slice variants with different ligand specificity. By untangling these layers, basic research into the chemistry and pharmacology of opioid receptors is guiding the way towards deciphering the mysteries of tolerance and physical dependence that have plagued the field and is providing a platform for the development of more effective and safer opioids.

Corticotropin-releasing factor (CRF), the stress-related neuropeptide, acts as a neurotransmitter in the brain norepinephrine nucleus, locus coeruleus (LC), to activate this system during stress. CRF shifts the mode of LC discharge from a phasic to a high tonic state that is thought to promote behavioral flexibility. To investigate this, the effects of CRF administered either intracerebroventricularly (30–300 ng, i.c.v.) or directly into the LC (intra-LC; 2–20 ng) were examined in a rat model of attentional set shifting. CRF differentially affected components of the task depending on dose and route of administration. Intracerebroventricular CRF impaired intradimensional set shifting, reversal learning, and extradimensional set shifting (EDS) at different doses. In contrast, intra-LC CRF did not impair any aspect of the task. The highest dose of CRF (20 ng) facilitated reversal learning and the lowest dose (2 ng) improved EDS. The dose–response relationship for CRF on EDS performance resembled an inverted U-shaped curve with the highest dose having no effect. Intra-LC CRF also elicited c-fos expression in prefrontal cortical neurons with an inverted U-shaped dose–response relationship. The number of c-fos profiles was positively correlated with EDS performance. Given that CRF excites LC neurons, the ability of intra-LC CRF to activate prefrontal cortical neurons and facilitate EDS is consistent with findings implicating LC-norepinephrine projections to medial prefrontal cortex in this process. Importantly, the results suggest that CRF release in the LC during stress facilitates shifting of attention between diverse stimuli in a dynamic environment so that the organism can adapt an optimal strategy for coping with the challenge.

Interventions to address the U.S. opioid crisis primarily target opioid use, misuse, and addiction, but because the opioid crisis includes multiple substances, the opioid specificity of interventions may limit their ability to address the broader problem of polysubstance use. Overlap of opioids with other substances ranges from shifts among the substances used across the lifespan to simultaneous co-use of substances that span similar and disparate pharmacological categories. Evidence suggests that nonmedical opioid users quite commonly use other drugs, and this polysubstance use contributes to increasing morbidity and mortality. Reasons for adding other substances to opioids include enhancement of the high (additive or synergistic reward), compensation for undesired effects of one drug by taking another, compensation for negative internal states, or a common predisposition that is related to all substance consumption. But consumption of multiple substances may itself have unique effects. To achieve the maximum benefit, addressing the overlap of opioids with multiple other substances is needed across the spectrum of prevention and treatment interventions, overdose reversal, public health surveillance, and research. By addressing the multiple patterns of consumption and the reasons that people mix opioids with other substances, interventions and research may be enhanced.

Stress-related psychiatric disorders are more prevalent in females than males, and this has been attributed to differences in stress sensitivity. As activation of the locus coeruleus (LC)-norepinephrine (NE) system is an important component of the stress response, this study compared LC responses to stress in female and male rats under different hormonal conditions in the halothane-anesthetized state. The mean basal LC discharge rate was similar between groups. However, the magnitude of LC activation elicited by hypotensive stress was substantially greater in females, regardless of hormonal status. The difference in stress sensitivity could be attributed to the differential postsynaptic sensitivity of LC neurons to corticotropin-releasing factor (CRF), which mediates LC activation by hypotension. CRF was 10-30 times more potent in activating LC neurons in female vs male rats. Interestingly, previous exposure to swim stress differentially regulated LC responses to CRF by sensitizing LC neurons of male, but not female, rats to CRF. The net effect of this was to abolish sex differences in LC sensitivity. Finally, CRF receptor (CRF-R) protein levels in the LC were greater in ovarectomized female vs male rats. This is the first study to demonstrate sex differences in the stress responsiveness of the brain noradrenergic system. Substantial sex differences were apparent in postsynaptic sensitivity to CRF and stress-induced regulation of postsynaptic sensitivity to CRF. These sex differences in the CRF regulation of the LC-NE system translate to a differential response to stress and may play a role in the increased vulnerability of females to stress-related psychiatric disorders.

Urodynamic status must interact with arousal and attentional processes so that voiding occurs under appropriate conditions. To elucidate the central encoding of this visceral demand, multisite recordings were made within a putative pontine-cortical micturition circuit from the pontine micturition center (PMC), locus coeruleus (LC) and medial prefrontal cortex (mPFC) during cystometry in unanesthetized rats. PMC neurons had homogeneous firing patterns, characterized by tonic activity and phasic bursts that were temporally associated with distinct phases of the micturition cycle. LC and cortical activation became synchronized 20-30 s prior to micturition. During this pre-micturition interval, a theta oscillation developed in the LC, the mPFC desynchronized and LC-mPFC coherence increased in the theta frequency range. The temporal offset between the shift in LC-mPFC network activity and micturition may allow time to disengage from ongoing behaviors unrelated to micturition and initiate specific voiding behaviors so that micturition occurs in environmentally and socially appropriate conditions. How do we know when we need to find a bathroom? As the bladder fills up, it sends signals to the brain to say that it needs emptying. But before the brain sends a message back to the bladder muscles telling them to contract to release urine, it first triggers a change in behavior. By increasing our alertness and arousing our senses, the brain ensures that we begin to look for a place where it is safe and appropriate to urinate. Only when we have found such a place will the brain tell the bladder to empty. Previous work has suggested that two brain regions play important roles in this process: the pontine micturition center (PMC) and its neighbor, the locus coeruleus. The PMC is thought to act as an on-off switch. When the bladder reaches a certain level of fullness the PMC activates, which tells the bladder muscles to contract. The locus coeruleus helps animals pay attention to important stimuli by making them more alert and energized whenever such stimuli are present. By recording the activity of neurons in the brains of rats while also measuring the pressure inside their bladders, Manohar et al. show that the PMC and the locus coeruleus work together to coordinate behavior and bladder emptying. Filling the bladder causes neurons in the locus coeruleus to activate in synchronized waves. This helps the locus coeruleus communicate with the brain’s outer layer, the cortex, leading to an increase in sensory alertness and arousal. This all happens before the bladder reaches the threshold fullness that activates the PMC, explaining why behavioral changes occur before urination. Manohar et al. show too that PMC neurons also activate when the rat is not urinating, suggesting that the PMC is more than an on-off switch. Healthy people experience the sensation of needing to empty their bladder well before the bladder is full, but people who do not receive these sensory signals may be unable to tell when they need to take action. This can lead to bedwetting in children and to incontinence in the elderly. Targeting the brain circuit that responds to bladder signals could lead to new treatments for these conditions.

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 μ-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.

Barrington's nucleus, the pontine micturition centre, is central to a circuit involved in the coordination of pelvic visceral activity with appropriate elimination behaviors. In this Review, the authors discuss the neuroanatomy of Barrington's nucleus and its projections, and the role of this nucleus in urological disorders. They also discuss a putative role for corticotropin-releasing factor as a potential mediator of these effects. The coordination of pelvic visceral activity with appropriate elimination behaviors is a complex task that requires reciprocal communication between the brain and pelvic organs. Barrington's nucleus, located in the pons, is central to a circuit involved in this function. Barrington's nucleus neurons project to both pelvic visceral motorneurons and cerebral norepinephrine neurons that modulate behavior. This circuit coordinates the descending limb of the micturition reflex with a central limb that initiates arousal and shifts the focus of attention to facilitate elimination behavior. The same circuitry that links the bladder and brain enables pathological processes in one target of the circuit to be expressed in the other. Urological disorders can, therefore, have cognitive and behavioral consequences by affecting components of this circuit; and in the opposing direction, psychosocial stressors can produce voiding dysfunctions and bladder pathology. The stress-related neuropeptide, corticotropin-releasing factor, which is prominent in Barrington's nucleus neurons, is a potential mediator of these effects. Key Points Barrington's nucleus in the pons coordinates the descending visceral limb of the micturition reflex with a central limb that initiates arousal and facilitates elimination behavior The stress-related neurotransmitter, corticotropin-releasing factor, regulates both limbs of the micturition reflex owing to its actions in the central and spinal projections of Barrington's nucleus neurons Pelvic visceral disorders can affect the major brain norepinephrine nucleus, the locus coeruleus and have neurobehavioral consequences Psychosocial stressors can produce voiding dysfunctions and bladder pathology via spinal projections of Barrington's nucleus neurons Neural circuits linking the brain and bladder provide a basis for the coexistence of bladder and neurobehavioral symptoms Pharmacological modulation of neurotransmitters expressed by Barrington's nucleus neurons—such as corticotropin-releasing factor—offers a novel approach for the treatment of bladder disorders

Corticotropin releasing factor (CRF) regulates physiological and behavioral responses to stress. Trauma in early life or adulthood is associated with increased CRF in the cerebrospinal fluid and heightened anxiety. Genetic variance in CRF receptors is linked to altered risk for stress disorders. Thus, both heritable differences and environmentally induced changes in CRF neurotransmission across the lifespan may modulate anxiety traits. To test the hypothesis that CRF hypersignaling is sufficient to modify anxiety-related phenotypes (avoidance, startle, and conditioned fear), we induced transient forebrain-specific overexpression of CRF (CRFOE) in mice (1) during development to model early-life stress, (2) in adulthood to model adult-onset stress, or (3) across the entire postnatal lifespan to model heritable increases in CRF signaling. The consequences of these manipulations on CRF peptide levels and behavioral responses were examined in adulthood. We found that transient CRFOE during development decreased startle habituation and prepulse inhibition, and increased avoidance (particularly in females) recapitulating the behavioral effects of lifetime CRFOE despite lower CRF peptide levels at testing. In contrast, CRFOE limited to adulthood reduced contextual fear learning in females and increased startle reactivity in males but did not change avoidance or startle plasticity. These findings suggest that forebrain CRFOE limited to development is sufficient to induce enduring alterations in startle plasticity and anxiety, while forebrain CRFOE during adulthood results in a different phenotype profile. These findings suggest that startle circuits are particularly sensitive to forebrain CRFOE, and that the impact of CRFOE may be dependent on the time of exposure.

Stress-related neuropsychiatric pathologies are more prevalent in females compared with males. An important component of the stress response is activation of the locus coeruleus (LC)-norepinephrine system. Because LC activation is tempered by endogenous opioid release during stress, the magnitude of opioid regulation of the LC could determine stress vulnerability. Here we report convergent evidence for decreased μ-opioid receptor (MOR) function in the female rat LC. The selective MOR agonist, DAMGO (10 pg), completely inhibited LC discharge of male but not female rats and DAMGO (30 pg) produced no further inhibition of female LC neurons. Consistent with a decreased maximum DAMGO response, MOR protein and mRNA expression were decreased in female compared with male LC. These molecular and cellular sex differences were associated with sexually distinct effects of LC-MOR activation on cognitive processing in an operant strategy-shifting task. Although DAMGO (10 pg intra-LC) increased the number of trials to reach criterion for both sexes, it increased the duration to complete the task and the total number of errors selectively in males. Specifically, DAMGO increased premature responses, regressive errors, and random errors in males and perseverative errors in females. The sexually distinct cognitive consequences of activating LC-MOR may contribute to sex differences in opioid abuse patterns and may guide sex-specific therapies. Finally, given evidence that endogenous opioids restrain stress-induced LC activation and promote recovery of activity to pre-stress levels, decreased MOR function in the female LC could contribute to LC-NE overactivity that underlies the hyperarousal symptoms of stress-related psychiatric diseases.