Insurmountable antagonism of human mu opioid receptors by buprenorphine is due to hemi-equilibrium.

Buprenorphine is an FDA approved drug for the treatment of opioid use disorder and is a long-lasting, low efficacy (partial) agonist of the μ opioid receptor. As a partial agonist, buprenorphine can act as either an agonist or an antagonist depending on the efficiency of the cellular signaling system. Here we investigated the antagonist properties of buprenorphine using a genetically-encoded biosensor to monitor cAMP levels in real time in HEK293 cells expressing a relatively low density of the human μ receptor.

14-3-3γ mediates the long-term inhibition of peripheral kappa opioid receptor antinociceptive signaling by norbinaltorphimine.

Long-term inhibition of kappa opioid receptor (KOR) signaling in peripheral pain-sensing neurons is a potential obstacle for development of peripherally-restricted KOR agonists that produce analgesia. Such a long-term inhibitory mechanism is invoked from activation of c-Jun N-terminal kinase (JNK) that follows a single injection of the KOR antagonist norbinaltorphimine (norBNI). This effect requires protein synthesis of an unknown mediator in peripheral pain-sensing neurons.

Age-related changes in peripheral nociceptor function.

Pain and pain management in the elderly population is a significant social and medical problem. Pain sensation is a complex phenomenon that typically involves activation of peripheral pain-sensing neurons (nociceptors) which send signals to the spinal cord and brain that are interpreted as pain, an unpleasant sensory experience. In this work, young (4-5 months) and aged (26-27 months) Fischer 344 x Brown Norway (F344xBN) rats were examined for nociceptor sensitivity to activation by thermal (cold and heat) and mechanical stimulation following treatment with inflammatory mediators and activators of transient receptor potential (TRP) channels.

"Feeling fat," disgust, guilt, and shame: Preliminary evaluation of a mediation model of binge-eating in adults with higher-weight bodies.

"Feeling fat" is a subjective state that theoretically contributes to the maintenance of binge eating (BE). However, feeling fat, and its relation to BE among individuals with higher-weight bodies, has been infrequently studied. This study proposes a momentary-level model in which negative moral emotion states (disgust, guilt, shame) mediate the association between feeling fat and binge eating.

Buprenorphine Exposure Alters the Development and Migration of Interneurons in the Cortex.

The misuse of opioids has reached epidemic proportions over the last decade, with over 2.1 million people in the United States suffering from substance use disorders related to prescription opioid pain relievers. This increase in opioid misuse affects all demographics of society, including women of child-bearing age, which has led to a rise in opioid use during pregnancy.

Long-term antagonism and allosteric regulation of mu opioid receptors by the novel ligand, methocinnamox.

Opioid overdose is a leading cause of death in the United States. The only treatment available currently is the competitive antagonist, naloxone (Narcan ). Although naloxone is very effective and has saved many lives, as a competitive antagonist it has limitations.

Regulating food labels in East Asia: A tale of two systems: Commentary on Negowetti et al. (2021).

The traditional role of food in promoting health and preventing illness is integral to many Asian cultures. This commentary provides a brief overview of health-related food products regulation in Asia. We cover regulations initiated to promote health and prevent chronic diseases and regulations of traditional medicine food products.

A qualitative examination of adolescent and parent perspectives on early identification and early response to eating disorders.

This qualitative study examined adolescent and caregiver perspectives on identification and early response in emerging eating disorders. Fifteen female-identified adolescents with an eating disorder diagnosis ( age = 15.20 years; 93% White; 20% Hispanic) and 12 caregivers (all biological parents: 1 father, 11 mothers; age = 51.

Bis-Quinolinium Cyclophane Blockers of SK Potassium Channels Are Antagonists of M3 Muscarinic Acetylcholine Receptors.

Dequalinium is used as an antimicrobial compound for oral health and other microbial infections. Derivatives of dequalinium, the bis-quinolinium cyclophanes UCL 1684 and UCL 1848, are high affinity SK potassium channel antagonists. Here we investigated these compounds as M3 muscarinic receptor (mACHR) antagonists.

Signaling characteristics and functional regulation of delta opioid-kappa opioid receptor (DOP-KOP) heteromers in peripheral sensory neurons.

Receptor heteromers often display distinct pharmacological and functional properties compared to the individual receptor constituents. In this study, we compared the properties of the DOP-KOP heteromer agonist, 6'-guanidinonaltrindole (6'-GNTI), with agonists for DOP ([D-Pen2,5]-enkephalin [DPDPE]) and KOP (U50488) in peripheral sensory neurons in culture and in vivo. In primary cultures, all three agonists inhibited PGE-stimulated cAMP accumulation as well as activated extracellular signal-regulated kinase 1/2 (ERK) with similar efficacy.

Longitudinal associations between emotion regulation skills, negative affect, and eating disorder symptoms in a clinical sample of individuals with binge eating.

Objective: Although deficits in emotion regulation have been implicated in the maintenance of binge eating, few prospective studies have examined longitudinal associations between emotion regulation and eating disorder symptoms, which are needed to test these theoretical models.

Method: Using a naturalistic design, the current study utilized longitudinal multilevel analyses to examine whether improvements in emotion regulation during treatment are associated with decreased binge eating frequency and eating disorder cognitions in a heterogeneous sample of adults with binge eating (N = 97). Analyses also accounted for between- and within-person differences in negative affect to inform specific targets for intervention.

Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity.

Constitutive receptor activity/inverse agonism and functional selectivity/biased agonism are 2 concepts in contemporary pharmacology that have major implications for the use of drugs in medicine and research as well as for the processes of new drug development. Traditional receptor theory postulated that receptors in a population are quiescent unless activated by a ligand. Within this framework ligands could act as agonists with various degrees of intrinsic efficacy, or as antagonists with zero intrinsic efficacy.

Allosterism within Opioid- Opioid Receptor Heteromers in Peripheral Sensory Neurons: Regulation of Opioid Agonist Efficacy.

There is abundant evidence for formation of G protein-coupled receptor heteromers in heterologous expression systems, but little is known of the function of heteromers in native systems. Heteromers of and opioid receptors (DOR-KOR heteromers) have been identified in native systems. We previously reported that activation of DOR-KOR heteromers expressed by rat pain-sensing neurons (nociceptors) produces robust, peripherally mediated antinociception.

Pharmacological augmentation of nicotinamide phosphoribosyltransferase (NAMPT) protects against paclitaxel-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) arises from collateral damage to peripheral afferent sensory neurons by anticancer pharmacotherapy, leading to debilitating neuropathic pain. No effective treatment for CIPN exists, short of dose-reduction which worsens cancer prognosis. Here, we report that stimulation of nicotinamide phosphoribosyltransferase (NAMPT) produced robust neuroprotection in an aggressive CIPN model utilizing the frontline anticancer drug, paclitaxel (PTX).

Negative affect and binge eating: Reconciling differences between two analytic approaches in ecological momentary assessment research.

Objective: Ecological momentary assessment (EMA) research has produced contradictory findings regarding the trajectory of negative affect after binge-eating episodes. Given the clinical implications, the objective of the current study was to reconcile these inconsistencies by comparing the two most commonly employed statistical approaches used to analyze these data.

Method: Data from two EMA studies were analyzed separately.

Regulation of δ Opioid Receptor-Mediated Signaling and Antinociception in Peripheral Sensory Neurons by Arachidonic Acid-Dependent 12/15-Lipoxygenase Metabolites.

The function of opioid receptors (DOR) expressed by peripheral pain-sensing neurons (nociceptors) is regulated by both cyclooxygenase- and lipoxygenase (LOX)-dependent arachidonic acid (AA) metabolites. Whereas cyclooxygenase metabolites enhance responsiveness, LOX metabolites elicit a refractory, nonsignaling state of the DOR receptor system for antinociceptive signaling. In this study, using high-performance liquid chromatography-tandem mass spectrometry analyses, we have found that the 12-/15-LOX metabolites, 12-hydroxyeicosatetraenoic acid (HETE) and 15-HETE, were elevated after treatment of adult rat primary sensory neuron cultures with AA.

Studies To Examine Potential Tolerability Differences between the 5-HT Receptor Selective Agonists Lorcaserin and CP-809101.

Lorcaserin (LOR) is a selective 5-HT receptor agonist that has been FDA approved as a treatment for obesity. The most frequently reported side-effects of LOR include nausea and headache, which can be dose limiting. We have previously reported that in the rat, while LOR produced unconditioned signs characteristic of nausea/malaise, the highly selective 5-HT agonist CP-809101 (CP) produced fewer equivalent signs.

The effects of psychotherapy treatment on outcome in bulimia nervosa: Examining indirect effects through emotion regulation, self-directed behavior, and self-discrepancy within the mediation model.

Objective: The purpose of this investigation was to examine the indirect effects of Integrative Cognitive-Affective Therapy (ICAT-BN) and Cognitive-Behavioral Therapy-Enhanced (CBT-E) on bulimia nervosa (BN) treatment outcome through three hypothesized maintenance variables: emotion regulation, self-directed behavior, and self-discrepancy.

Method: Eighty adults with BN were randomized to 21 sessions of ICAT-BN or CBT-E. A regression-based bootstrapping approach was used to test the indirect effects of treatment on outcome at end of treatment through emotion regulation and self-directed behavior measured at mid-treatment, as well as the indirect effects of treatment at follow-up through emotion regulation, self-directed behavior, and self-discrepancy measured at end of treatment.

Trajectories of higher- and lower-order dimensions of negative and positive affect relative to restrictive eating in anorexia nervosa.

Despite robust support for the role of affect in the maintenance of binge eating and purging, the relationship between affect and restrictive eating remains poorly understood. To investigate the relationship between restrictive eating and affect, ecological momentary assessment data from 118 women with anorexia nervosa (AN) were used to examine trajectories of higher-order dimensions of negative affect (NA) and positive affect (PA), as well as lower-order dimensions of NA (Fear, Guilt) and PA (Joviality, Self-Assurance) relative to restrictive eating. Affect trajectories were modeled before and after restrictive eating episodes and AN subtype was examined as a moderator of these trajectories.

Constitutive Desensitization of Opioid Receptors in Peripheral Sensory Neurons.

Opioid receptors expressed by peripheral pain-sensing neurons are functionally inactive for antinociceptive signaling under most basal conditions; however, tissue damage or exposure to inflammatory mediators (e.g., bradykinin) converts these receptors from a nonresponsive state to a functionally competent state.

Long-Term Reduction of Kappa Opioid Receptor Function by the Biased Ligand, Norbinaltorphimine, Requires c-Jun N-Terminal Kinase Activity and New Protein Synthesis in Peripheral Sensory Neurons.

A single administration of the κ opioid receptor (KOR) antagonist, norbinaltorphimine (norBNI), produces long-term reduction in KOR function in heterologous expression systems and brain that is mediated by activation of c-Jun N-terminal kinase (JNK). In this study, we examined the long-term effects of norBNI on adult rat peripheral sensory neurons in vivo and ex vivo. Following a single intraplantar (i.

Self-weighing behavior in individuals with eating disorders.

Objective: To describe the frequency of self-weighing and reactions to prescribed weekly weighing among individuals with eating disorder (ED) diagnoses, and to compare individuals weighing more or less frequently on mass index (BMI) and the Eating Disorder Examination (EDE) subscales.

Method: Baseline EDE and demographics from five studies (N = 758).

Results: Self-weighing was most frequent among individuals with anorexia nervosa (AN), followed by those with bulimia nervosa (BN) and binge eating disorder (BED).

Predictors and moderators of treatment outcome in a randomized clinical trial for adults with symptoms of bulimia nervosa.

Objective: This study examined predictors and moderators of outcome in 2 treatments for bulimia nervosa (BN).

Method: Eighty adults with BN symptoms at 1 of 2 sites were randomized to 21 sessions of integrative cognitive-affective therapy for BN (ICAT-BN) or enhanced cognitive behavior therapy (CBT-E). Generalized linear models examined predictors and moderators of improvements in bulimic behavior and eating disorder psychopathology at end of treatment (EOT) and 4-month follow-up (FU).

Functional selectivity of kappa opioid receptor agonists in peripheral sensory neurons.

Activation of kappa opioid receptors (KORs) expressed by peripheral sensory neurons that respond to noxious stimuli (nociceptors) can reduce neurotransmission of pain stimuli from the periphery to the central nervous system. We have previously shown that the antinociception dose-response curve for peripherally restricted doses of the KOR agonist (-)-(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50488) has an inverted U shape. Here, we found that the downward phase of the U50488 dose-response curve was blocked by an inhibitor of extracellular signal-regulated kinase (ERK) activation U0126.