Simple strategies can reduce harms from misuse of pharmaceutical opioids.

The Philip S. Protoghese Medicinal Chemistry Lectureship: Addressing the "Core Issue" in the Design of Estrogen Receptor Ligands.

To assess the effect of the calcitonin gene-related peptide (CGRP) receptor antagonist, telcagepant, on the haemodynamic response to sublingual nitroglycerin (NTG). Twenty-two healthy male volunteers participated in a randomized, placebo-controlled, double-blind, two-period, crossover study. Subjects received 500 mg telcagepant or placebo followed, 1.5 h later, by 0.4 mg NTG. To ...

[(11) C] P943 is a recently developed PET radiotracer for serotonin 5-HT(1B) receptors. We characterized a number of its in vivo pharmacokinetic properties, including the evaluation of its two stereo-isomers, saturability of specific binding, selectivity for 5-HT(1B) and 5-HT(1D) receptors and vulnerability to pharmacologically induced increases in endogenous 5-HT levels. ...

As there is evidence for an anti-inflammatory efficacy of histamine H(4) receptor (H4R) selective antagonists, we aimed at testing the efficacy of the H4R antagonists JNJ7777120 and JNJ28307474 in comparison with histamine H(1) receptor (H1R) antagonists hydroxyzine and cetirizine for skin lesion prevention in a canine model of acute atopic ...

The cannabinoid system appears to play a critical facilitative role in mediating the reinforcing effects of nicotine and relapse to nicotine-seeking behaviour in abstinent subjects based on the actions of cannabinoid (CB) receptor antagonists. However, the effects of CB receptor stimulation on nicotine self-administration and reinstatement have not been systematically ...

Animal studies indicate that dopamine pathways in the ventral striatum code for the motivational salience of both rewarding and aversive stimuli, but evidence for this mechanism in humans is less established. We have developed a functional magnetic resonance imaging (fMRI) model which permits examination of the neural processing of both ...

Migraine remains one of the most prevalent and disabling neurological disorders that often affects a person during their most productive years. Migraine afflicts approximately 11% of the adult population globally, causes substantial disability, which translates into lost productivity both at home and at work. Clearly there remains a need for ...

Migraine has a 1-year prevalence of 10% and high socioeconomic costs. Despite recent drug developments, there is a huge unmet need for better pharmacotherapy. In this review we discuss promising anti-migraine strategies such as calcitonin gene-related peptide (CGRP) receptor antagonists and 5-hydroxytrypamine (5-HT)(1F) receptor agonists, which are in late-stage development. ...

A growing body of evidence has demonstrated a role for group II metabotropic glutamate receptors (mGluRs) in the reinforcing effects of cocaine. These receptors are important given their location in limbic-related areas, and their ability to control the release of glutamate and other neurotransmitters. They are also potential targets for ...

Neuroadaptation in the nucleus accumbens (NAc), a central component of the mesolimbic dopamine (DA) system, has been implicated in the development of cocaine-induced psychomotor sensitization and relapse to cocaine seeking. However, little is known about the cellular and synaptic mechanisms underlying such adaptation. Using a mouse model of behavioral sensitization, ...

Within the trigeminal ganglion, crosstalk between neurons and satellite glial cells (SGCs) contributes to neuronal sensitization and transduction of painful stimuli, including migraine pain, at least partly through activation of purinergic receptor mechanisms. We previously showed that the algogenic mediator bradykinin (BK) potentiates purinergic P2Y receptors on SGCs in primary ...

The following brief overview reflects our own opinion of where the most likely advances to treating pain (unrelated to IBS and migraine) may come from with respect to ligands directly interacting with specific 5-HT receptors. It is fully appreciated, and possibly more likely, that 5-HT plays a modulatory role in ...

This application claims dual receptor specificity antihistamines, active as H(1) and H(3) antagonists, which additionally have a long duration of action that renders them suitable for once daily administration via inhalation for the treatment of allergic rhinitis. The compounds lack CNS penetration and have a high affinity for both histamine ...

The methods used to assess cardiac parasympathetic (cardiovagal) activity and its effects on the heart in both humans and animal models are reviewed. Heart rate (HR)-based methods include measurements of the HR response to blockade of muscarinic cholinergic receptors (parasympathetic tone), beat-to-beat HR variability (HRV) (parasympathetic modulation), rate of post-exercise ...

Orexin-A and -B (also known as hypocretin-1 and -2) are neuropeptides produced in the lateral hypothalamus that promote many aspects of arousal through the OX1 and OX2 receptors. In fact, they are necessary for normal wakefulness, as loss of the orexin-producing neurons causes narcolepsy in humans and rodents. This has ...

Subtype 2 serotonin (5-hydroxytryptamine, 5-HT) receptors are major drug targets for schizophrenia, feeding disorders, perception, depression, migraines, hypertension, anxiety, hallucinogens, and gastrointestinal dysfunctions. (1) We report here the predicted structure of 5-HT2B and 5-HT2C receptors bound to highly potent and selective 5-HT2B antagonist PRX-08066 3, (pKi: 30 nM), including the ...

The polypharmacological approach to the treatment of postoperative pain has become routine in an attempt to minimize the adverse side effects of opioids. Magnesium sulphate is a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor and thus can modify nociceptive modulation. Intravenous administration of magnesium sulphate can improve postoperative analgesia and ...

Cocaine-induced changes in D(2) receptors have been implicated in the expression of sensitized behavioral responses and addiction-like behaviors; however, the influence of D(3) receptors is less clear. To characterize the effects of repeated cocaine administration on the sensitivity of rats to D(2)- and D(3)-mediated behaviors, as well as the binding ...

Activation of histamine H3 receptors blocks the release of peptides responsible for headache. Our objective was to investigate the association between the genotypes of A280V polymorphism in the H3 receptor and migraine risk. We evaluated the frequency of the genotypes of A280V, polymorphism A280V and allelic variants of H3 receptor ...

Cocaine is an indirect sympathomimetic agent that acts in the nervous system to block the presynaptic reuptake of serotonin and catecholamines (dopamine, norepinephrine and epinephrine) and to increase their bioavailability at the post-synaptic receptors. The association of cocaine and hyponatremia has not been reported in adults. We describe a case ...

The atypical antidepressant, mirtazapine enhances noradrenergic transmission, but its effects on serotonergic transmission remain to be clarified. The present study determined the effects of acute and chronic administration of mirtazapine on serotonergic transmissions in raphe nuclei and their innervation regions, frontal and entorhinal cortex, using multiple-probes microdialysis with real-time PCR ...

In our ongoing efforts to develop CGRP receptor antagonists for the treatment of migraine, we aimed to improve upon telecagepant by targeting a compound with a lower projected clinical dose. Imidazoazepanes were identified as potent caprolactam replacements and SAR of the imidazole yielded the tertiary methyl ether as an optimal ...

We have previously shown that only four 15-min social interaction episodes with a male adult conspecific reversed cocaine conditioned place preference (CPP) even despite continuing CPP training with cocaine. In the present study, we investigated if BD1047, a sigma1 receptor antagonist that has been shown to inhibit the expression of ...

RATIONALE: γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the modulation of central reward processes. Acute or chronic administration of GABA(B) receptor agonists or positive modulators decreased self-administration of various drugs of abuse. Furthermore, GABA(B) receptor agonists inhibited cue-induced reinstatement of nicotine- and ...

The endocannabinoid system is a potential target for therapeutic intervention of substance abuse. Cannabinoid CB1 receptor antagonist decreases intravenous methamphetamine self-administration in animal models. This study examined whether the nucleus accumbens (NAcc) is a site of interaction between methamphetamine and the CB1 receptor antagonist AM251. Male Sprague-Dawley rats were trained ...

Adenosine acts in parallel as a neuromodulator and as a homeostatic modulator in the central nervous system. Its neuromodulatory role relies on a balanced activation of inhibitory A(1) receptors (A1R) and facilitatory A(2A) receptors (A2AR), mostly controlling excitatory glutamatergic synapses: A1R impose a tonic brake on excitatory transmission, whereas A2AR ...

The parasympathetic signalling molecules acetylcholine, pituitary adenylate cyclase activating peptide-38 (PACAP38) and vasoactive intestinal peptide (VIP) may be released from parasympathetic fibres and activate sensory nerve fibres during migraine attacks. Recently, it was shown that VIP does not induce migraine-like attacks in migraine patients. Interestingly, PACAP38 activates the same VPAC ...

Drugs of abuse are initially used because of their rewarding properties. As a result of repeated drug exposure, sensitization to certain behavioral effects of drugs occurs, which may facilitate the development of addiction. Recent studies have implicated the metabotropic glutamate receptor 5 (mGlu5 receptor) in drug reward, but its role ...

Cocaine exhibits preferential (~15-fold) affinity for σ₁ over σ₂ sigma receptors, and previous research has shown an interaction of σ₁ receptor-selective ligands and cocaine's behavioral effects. The present study investigated the effect of the putative sigma receptor agonist SA 4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride) on cocaine's locomotor stimulatory and discriminative stimulus properties. ...

The TRPA1 receptor is a member of the transient receptor potential (TRP) family of ion channels expressed in nociceptive neurons. TRPA1 receptors are targeted by pungent compounds from mustard and garlic and environmental irritants such as formaldehyde and acrolein. Ingestion or inhalation of these chemical agents causes irritation and burning ...

Esophageal mechanoreceptors, i.e. muscular slowly adapting tension receptors and mucosal rapidly adapting touch receptors, mediate different sets of reflexes. The aim of this study was to determine the medullary vagal nuclei involved in the reflex responses to activation of these receptors. Thirty-three cats were anesthetized with alpha-chloralose and the esophagus ...

Migraine is considered a neurovascular disease affecting more than 10% of the general population. Currently available drugs for the acute treatment of migraine are vasoconstrictors, which have limitations in their therapeutic use. The calcitonin gene-related peptide (CGRP) has a key role in migraine, where levels of CGRP are increased during ...

The endogenous brain serotonin (5-HT) system is believed to have an important modulatory influence in mediating drug reward and seeking mechanisms. Data from preclinical behavioral studies have provided emerging evidence that 5-HT(6) receptors, among other 5-HT receptors, may play a significant role in the mechanisms of action of psychostimulant addicted ...

An exaggerated exercise pressor reflex (EPR) contributes to exercise intolerance and excessive sympatho-excitation in the chronic heart failure (CHF) state. However, the components of this reflex that are responsible for the exaggerated EPR in CHF remain unknown. To determine whether muscle afferent function is altered in CHF, we recorded the ...

We have previously described the physiological and morphological properties of the cough receptors and their sites of termination in the airways and centrally in the nucleus tractus solitarius (nTS). In the present study, we have addressed the hypothesis that the primary central synapses of the cough receptors subserve an essential ...

Sympathetic nerve hyperactivity has been associated with hypertension and heart failure and their cardiovascular complications. The α2-adrenergic receptors have been proposed to play a prominent role in the control of sympathetic neural output, and their malfunction to constitute a potential central mechanism for sympathetic hyperactivity of essential hypertension. Reports on ...

glucagon-like peptide 1 (GLP-1) is an incretin hormone released from the gut in response to food intake. Whereas GLP-1 acts in the periphery to inhibit glucagon secretion and stimulate insulin release, it also acts in the central nervous system to mediate autonomic control of feeding, body temperature, and cardiovascular function. ...

Non-ergot-type dopamine receptor agonists such as ropinirole are used for the treatment of Parkinson disease, but they occasionally show serious side effects including sleep attacks and daytime sleepiness. These symptoms are reminiscent of narcolepsy, a major sleep disorder. Because narcolepsy is thought to result from deficiency of a hypothalamic neuropeptide ...

Intense air-conducted sound (ACS) elicits an ocular vestibular-evoked myogenic potential (oVEMP), and it has been suggested that it does so by stimulating saccular receptors and afferents in the inferior vestibular nerve and so activating a crossed sacculo-ocular pathway. Bone conducted vibration (BCV) also elicits an oVEMP probably by activating utricular ...

Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how ...

Anatomical studies have shown that the paraventricular nucleus of the thalamus (PVT) innervates areas of the forebrain involved in the expression and regulation of emotional behaviors including fear and anxiety. In addition, the PVT is densely innervated by fibers containing orexin-A (OXA) and orexin-B (OXB), peptides that are well-known for ...

Coughing protects and clears the airways and lungs of inhaled irritants, particulates, pathogens, and accumulated secretions. An initial urge to cough, and an almost binary output suggests gating mechanisms that encode and modulate this defensive reflex. Whether this "gate" has a physical location for the physiological barrier it poses to ...

The orexins are neurohormones that, in concert with their cognate receptors, regulate a number of important physiological processes, including feeding, sleep, reward seeking and energy homeostasis. The orexin receptors have recently emerged as important drug targets. This review provides an overview of recent development in deciphering the biology of orexin ...

Touch is initiated by diverse somatosensory afferents that innervate the skin. The ability to manipulate and classify receptor subtypes is prerequisite for elucidating sensory mechanisms. Merkel cell-neurite complexes, which distinguish shapes and textures, are experimentally tractable mammalian touch receptors that mediate slowly adapting type I (SAI) responses. The assessment of ...

The control of breathing depends critically on sensory inputs to the central pattern generator of the brainstem, arising from peripheral arterial chemoreceptors located principally in the carotid bodies (CBs). The CB receptors, i.e. glomus or type I cells, are excited by chemical stimuli in arterial blood, particularly hypoxia, hypercapnia, acidosis ...

Orexin A (OXA) and orexin B (OXB) are recently discovered neuropeptides that appear to play a role in various distinct functions such as arousal and the sleep-wake cycle as well as on appetite and regulation of feeding and energy homeostasis. Orexins were first described as neuropeptides expressed by a specific ...

AIMS: The Transient Receptor Potential Melastatin (TRPM)8 channel, activated by menthol and cool temperatures, has been proposed to be a cool receptor involved in mediation of the bladder response in the diagnostic ice water test. We examined the expression of TRPM8 in the rat skin and investigated if stimulation of ...

IMPORTANCE OF THE FIELD: The orexin neuropeptide system plays a central role in maintaining arousal and wakefulness. It has been demonstrated that small molecule antagonists to the orexin receptors promote sleep in preclinical species and in patients with insomnia. AREAS COVERED IN THIS REVIEW: This review provides a summary of ...

Orexin A (OXA) and orexin B (OXB) are recently discovered neuropeptides that appear to play a role in various distinct functions such as arousal and the sleep-wake cycle as well as on appetite and regulation of feeding and energy homeostasis. Orexins were first described as neuropeptides expressed by a specific ...