Mu-opioid Antagonist Research Articles

10.2 Effect of an Opioid Receptor Antagonist on Stimulant Treatment of Adults With Attention-Deficit/Hyperactivity Disorder

Preclinical studies have shown that methylphenidate (MPH) activates mu opioid receptors, which are linked to euphoria. It is possible that mu opioid antagonists, such as naltrexone, may attenuate the euphoric effects of stimulants, thereby minimizing their abuse potential. The main aim of this study was to assess whether the combination of naltrexone with MPH is safe and effective and whether it preserves the clinical benefits of stimulants. We hypothesized that the coadministration of naltrexone would not affect the therapeutic potency of stimulants in the treatment of subjects with ADHD.

Can alcohol-dependent patients really reduce their alcohol consumption over time?

IntroductionTreatment of alcohol dependent patients is moderately successful but it only reaches about 10% of the population in need. A new harm reduction strategy aims at abstinence in the long run but claims to benefit patients already early on by reducing their alcohol consumption.ObjectivesA brief outline of the debate on abstinence versus controlled drinking will be followed reporting several RCTs striving for reduced drinking in alcohol dependent patients.AimsThe participant will find guidance whether and how to treat patients following this new approach.ResultsStudies testing behavioural treatments and counselling (MATCH, UKATT) indicate that a reduction over time is possible. Using nalmefene (a mu and delta opioid antagonist and a partial agonist) RCTs with more than 2500 patients were performed showing a benefit over placebo. On this basis the EMA approved this drug for the reduction of alcohol consumption in alcohol dependent patients. Other compounds such as naltrexone showed similar effects in smaller trials but are not approved for reduction. More studies testing further compounds are underway.ConclusionsThis new approach has the potential to lower the barriers which to date prevent many patients from accepting treatment for their alcohol problems. Two research questions warrant further study: (1) does the reduction in alcohol consumption translate into health and other benefits, and (2) are there specific subgroups of patients who benefit more than others. Preliminary answers will be given in the lecture.Disclosure of interestThe author has not supplied his declaration of competing interest.

Nalmefene for the treatment of alcohol use disorders: recent data and clinical potential

ABSTRACTIntroduction: Few pharmacotherapies are available for alcoholism. Numerous studies indicate the involvement of the opioid-endorphin system in mediating the reinforcing effects of alcohol via dopaminergic neurons. The opioid antagonist naltrexone was found to be effective in alcohol treatment, and the European Medicines Agency has now approved the mu-opioid antagonist und partial kappa agonist nalmefene.Areas covered: This article presents background information on the chemistry of nalmefene and pre-clinical and clinical findings. The three relevant Phase III studies, all of which followed a harm-reduction, “as needed” approach and found reduced alcohol consumption with nalmefene 18 (20) mg, are discussed in detail.Expert opinion: The integration of the “as needed” approach into conventional psychosocial alcohol therapies may be challenging but offers the opportunity to reach otherwise not treated patients. Nalmefene is the first medication to be approved specifically in this indication and seems to be most suitable for patients with alcohol misuse or a rather low physical dependence on alcohol who do not require immediate detoxification or inpatient treatment. Although a categorical distinction between patients who want to stop heavy drinking or drinking at all over time may be somewhat hypothetical, nalmefene offers new treatment options to patients with alcohol use disorder.

Treatment-refractory substance use disorder: Focus on alcohol, opioids, and cocaine

Substance use disorders are common, but only a small minority of patients receive adequate treatment. Although psychosocial therapies are effective, relapse is common. This review focusses on novel pharmacological and other treatments for patients with alcohol, opioid, or cocaine use disorders who do not respond to conventional treatments.Disulfiram, acamprosate, and the opioid antagonist naltrexone have been approved for the treatment of alcoholism. A novel, “as needed” approach is the use of the mu-opioid antagonist and partial kappa agonist nalmefene to reduce alcohol consumption. Other novel pharmacological approaches include the GABA-B receptor agonist baclofen, anticonvulsants such as topiramate and gabapentin, the partial nicotine receptor agonist varenicline, and other drugs. For opioid dependence, opioid agonist therapy with methadone or buprenorphine is the first-line treatment option. Other options include oral or depot naltrexone, morphine sulfate, depot or implant formulations, and heroin (diacetylmorphine) in treatment-refractory patients. To date, no pharmacological treatment has been approved for cocaine addiction; however, 3 potential pharmacological treatments are being studied, disulfiram, methylphenidate, and modafinil. Pharmacogenetic approaches may help to optimize treatment response in otherwise treatment-refractory patients and to identify which patients are more likely to respond to treatment, and neuromodulation techniques such as repeated transcranial magnetic stimulation and deep brain stimulation also may play a role in the treatment of substance use disorders.Although no magic bullet is in sight for treatment-refractory patients, some novel medications and brain stimulation techniques have the potential to enrich treatment options at least for some patients.

Inhibition of Inflammatory and Neuropathic Pain by Targeting a Mu Opioid Receptor/Chemokine Receptor5 Heteromer (MOR-CCR5)

Chemokine release promotes cross-talk between opioid and chemokine receptors that in part leads to reduced efficacy of morphine in the treatment of chronic pain. On the basis of the possibility that a MOR-CCR5 heteromer is involved in such cross-talk, we have synthesized bivalent ligands (MCC series) that contain mu opioid agonist and CCR5 antagonist pharmacophores linked through homologous spacers (14-24 atoms). When tested on lipopolysaccharide-inflamed mice, a member of the series (MCC22; 3e) with a 22-atom spacer exhibited profound antinociception (i.t. ED50 = 0.0146 pmol/mouse) that was 2000× greater than morphine. Moreover, MCC22 was ~3500× more potent than a mixture of mu agonist and CCR5 antagonist monovalent ligands. These data strongly suggest that MCC22 acts by bridging the protomers of a MOR-CCR5 heteromer having a TM5,6 interface. Molecular simulation studies are consistent with such bridging. This study supports the MOR-CCR5 heteromer as a novel target for the treatment of chronic pain.

The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.

RationaleUsing the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice.ObjectiveWe test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy.MethodsThirty-six C57BL/6J mice were tested in a DID procedure. In 2-day cycles, animals experienced one baseline, injection-free session, and one test session when they received two injections, one of test drug and one placebo. All animals received GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min pre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c. 10 min pre-treatment) in a cross-over design. Receptor occupancies following the same doses were determined ex vivo in separate groups by autoradiography, using [3H]DAMGO. Binding in the region of interest was measured integrally by computer-assisted microdensitometry and corrected for non-specific binding.ResultsBoth GSK1521498 and naltrexone dose-dependently decreased ethanol consumption. When drug doses were matched for 70–75 % receptor occupancy, GSK1521498 3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol consumption than naltrexone 0.1 mg/kg, s.c. Both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test of conditioned taste aversion, GSK1521498 (3 mg/kg) reduced sucrose consumption 24 h following exposure to a conditioning injection.ConclusionsBoth opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-015-3995-x) contains supplementary material, which is available to authorized users.

Combined Restitutive Therapy for Treatment of Immunosuppressive Refractory Crohn Disease

Crohn’s Disease (CD) is believed to be the result of dys-regulated interactions between a genetically susceptible host and their commensal gut microbiota (1). CD affects over 600,000 Americans and treatment still faces many challenges (2). Pharmacotherapy centers on the use of anti-inflammatories and immunosuppressants (3). However, a sub-set of patients with CD are refractory to immunosuppressive therapy. Recent studies have implicated defects in autophagy and bacterial killing as a possible etiology leading to host-microbe dysregulation (4). This could explain the lack of response to immunosuppression seen in these CD patients. A recent study in adults with CD showed the potential for granulocyte-macrophage colony stimulating factor (GM-CSF) to enhance bacterial killing and restore intestinal homeostasis (5), but very little data exists in pediatric patients (6). Another study reports a role for low-dose naltrexone (LDN, a mu opioid antagonist) in helping restore the epithelial barrier in active CD (7). The mechanism of action of LDN is thought to be through activation of endogenous opioid signaling (8). Recent murine studies have shown that direct mu opioid receptor (MOR) activation can enhance intestinal epithelial healing and prevent epithelial apoptosis (9). Here, we report a combined intestinal-restitutive approach using GM-CSF and loperamide (a peripheral MOR agonist) to induce and maintain remission in a 17-year-old CD patient.

Recent Developments in Pharmacotherapy of Alcoholism.

Alcohol use disorders are common, but only a small minority of patients receive adequate treatment. Cognitive-behavioural therapies, motivational enhancement interviewing and brief interventions are established treatments, but few pharmacotherapies are available. This narrative focuses on the neurobiological basis of alcohol use disorders and on emerging drugs that either have recently been approved or look likely to find their way into clinical practice. To date, acamprosate and the opioid antagonist naltrexone have been approved for treatment of alcohol dependence. Recently, the mu-opioid antagonist and partial kappa agonist nalmefene was approved by the European Medicines Agency for reduction of alcohol consumption. Novel clinical approaches include drugs established for other indications such as the GABA-B receptor agonist baclofen, anticonvulsants such as topiramate and gabapentin, the partial nicotine receptor agonist varenicline, and other drugs. Developments in pharmacogenetics are discussed. The development of pharmaceutical agents to treat alcohol use disorders has lagged behind that of depression and schizophrenic psychosis and is hampered by an incomplete understanding of the neurobiological background. Pharmacogenetics may improve treatment in the future.

Current topical and systemic therapies for itch.

Itch is a common distressing symptom which may be caused by multifactorial aetiologies including inflammatory skin diseases, systemic diseases, neuropathic conditions and psychogenic disorders. Itch is a term used synonymously with pruritus and is defined as acute if it lasts less than 6 weeks or chronic if it persists for more than 6 weeks. It can have the same impact on the quality of life as chronic pain and shares many of the same pathophysiological pathways. Depending on the aetiology of the itch, different pathogenic mechanisms have been postulated with a number of mediators identified. These include histamine, leukotrienes, proteases, neuropeptides, cytokines and opioids, which may activate peripheral itch-mediating C-fibres via receptors on the nerve terminals and central neuronal pathways. Therefore, there is no single universally effective anti-itch treatment available. First-line treatments for itch include topical therapies, such as emollients, mild cleansers (low pH), topical anaesthetics, steroids, calcineurin inhibitors and coolants (menthol). Treatment with systemic therapies can vary according to the aetiology of the chronic itch. Non-sedating antihistamines are helpful in conditions such as urticaria where the itch is primarily histamine mediated. Although the itch of eczema is not mediated by histamine, sedating antihistamines at night are helpful to break the itch-scratch cycle. Chronic itch may also be treated with other systemic therapies, such as anticonvulsants, antidepressants as well as mu-opioid antagonists, kappa-opioid agonists and phototherapy, depending on the cause of the itch. This article summarises the topical and systemic therapies available with our current understanding of the pathophysiology of itch.

Naloxegol: New treatment for opioid-induced constipation

Naloxegol: New treatment for opioid-induced constipation

P.2.a.011 In vivo electrophysiological characterisation of the acute effects of brexpiprazole administration on monoamine systems

and overdose potential. One strategy to increase the utility of opioids is to balance the activity of known partial or full mu opioid agonists with a pharmacologically active mu opioid antagonist. It is hypothesized that such a combination would modulate the pharmacodynamic effects of the agonist molecule so as to minimize its potential for abuse and overdose while preserving therapeutic efficacy. Previously, it has been demonstrated that co-administration of buprenorphine with samidorphan dose-dependently attenuated buprenorphine-induced elevations of extracellular dopamine and its metabolites in the nucleus accumbens and medial prefrontal cortex in rats (Deaver, et al., ACNP 2013). Corticosterone-induced decreases in saccharin consumption and the forced swim test are models commonly used to study the antidepressant-like effects of drugs. In the first model, rats were induced into a depressive-like state with chronic exposure to corticosterone, as indicated by a decrease in saccharin consumption. In the forced swim test, Wistar-Kyoto rats were used because they are a spontaneously hypertensive strain that demonstrate endogenous hormonal and behavioral abnormalities often used in nonclinical models of behavioral despair. Antidepressant drugs reverse corticosterone-induced decreases in saccharin consumption and reduce immobility time in the forced swim test. Here, two doses of samidorphan (0.3mg/kg and 3.0mg/kg) were administered with a fixed dose of buprenorphine (0.1mg/kg) and data were analyzed using one-way analysis of variances. Buprenorphine, combined with 0.3mg/kg samidorphan, reversed corticosterone-induced decreases in saccharin consumption and decreased immobility in the forced swim test. However, when buprenorphine was combined with the higher dose of samidorphan (3.0mg/kg), the positive effects observed with the lower dose were reversed in both the saccharin consumption test and forced swim test. Thus, balanced modulation of opioid pharmacology may unlock the potential therapeutic value of known opioids by improving their safety. Together, the current data suggest that modulation of mu receptor activity plays an important role in the observed effects in these rat models of depression-like behavior.

Targeting putative mu opioid/metabotropic glutamate receptor-5 heteromers produces potent antinociception in a chronic murine bone cancer model

The therapeutic management of chronic pain associated with many cancers is problematic due to the development of tolerance and other adverse effects during the disease progression. Recently we reported on a bivalent ligand (MMG22) containing both mu agonist and mGluR5 antagonist pharmacophores that produced potent antinociception in mice with LPS-induced acute inflammatory pain via a putative MOR-mGluR5 heteromer. In the present study we have investigated the antinociception of MMG22 in a mouse model of bone cancer pain to determine its effectiveness in reducing this type of chronic nociception. There was a 572-fold increase in the potency of MMG22 over a period of 3–21 days that correlated with the progressive increase in hyperalgesia induced by bone tumor growth following implantation of fibrosarcoma cells in mice. The enhancement of antinociception with the progression of the cancer is possibly due to inhibition of NMDA receptor-mediated hyperalgesia via antagonism of mGluR5 and concomitant activation of MOR by the MMG22-occupied heteromer. Notably, MMG22 was 3.6-million-fold more potent than morphine at PID 21. Since MMG22 exhibited a 250,000-times greater potency than that of a mixture of the mu opioid (M19) agonist and mGluR5 antagonist (MG20) monovalent ligands, the data suggest that targeting the putative MOR-mGluR5 heteromer is far superior to univalent interaction with receptors in reducing tumor-induced nociception. In view of the high potency, long duration (>24h) of action and minimal side effects, MMG22 has the potential to be a superior pharmacological agent than morphine and other opiates in the treatment of chronic cancer pain and to serve as a novel pharmacologic tool.

Opioid Antagonists

Opioid Antagonists

Central effects of ethanol interact with endogenous mu-opioid activity to control isolation-induced analgesia in maternally separated infant rats

Endogenous opioid activity plays an important role in ethanol consumption and reinforcement in infant rats. Opioid systems are also involved in mediation and regulation of stress responses. Social isolation is a stressful experience for preweanling rats and changes the effects of ethanol through opioid-dependent mechanisms. The present study assessed effects of intracisternal (i.c.) administration of a selective mu-opioid antagonist (CTOP) and i.p. administration of a nonspecific opioid antagonist (naloxone) on voluntary intake and behavior in socially isolated 12-day-old (P12) pups treated with 0.5g/kg ethanol. Voluntary intake of 0.1% saccharin or water, locomotion, rearing activity, paw licking and grooming were assessed during short-term isolation from littermates (STSI; 8-min duration). Thermal nociceptive reactivity was measured before and after this intake test, with normalized differences between pre- and post-test latencies of paw withdrawal from a hot plate (49°C) used as an index of isolation-induced analgesia (IIA).Results indicated several effects of social isolation and ethanol mediated through the mu-opioid system. Effects of low dose ethanol (0.5g/kg) and voluntary consumption of saccharin interacted with endogenous mu-opioid activity associated with STSI. Blockade of mu-opioid receptors on saccharin consumption and paw licking-grooming affected intoxicated animals. Low dose ethanol and ingestion of saccharin blunted effects of CTOP on rearing behavior and nociceptive reactivity. Central injections of CTOP stimulated paw licking and grooming dependent on ethanol dose and type of fluid ingested. Ethanol selectively increased saccharin intake during STSI in females, naloxone and CTOP blocked ethanol-mediated enhancement of saccharin intake. We suggest that enhancement of saccharin intake by ethanol during STSI is the product of synergism between isolation-induced mu-opioid activity that increases the pup's sensitivity to appetitive taste stimulation and the anxiolytic effects of 0.5g/kg ethanol that decreases behaviors otherwise competing with independent ingestive activity.

Nalmefene for the treatment of alcohol dependence: a current update

To date, few pharmacotherapies have been established for the treatment of alcoholism. There is a plethora of research concerning the involvement of the opioid-endorphin system in mediating the reinforcing effects of alcohol. The opioid antagonist naltrexone has been found to be effective in alcohol treatment. In addition, the mu-opioid antagonist and partial kappa agonist nalmefene was recently approved by the European Medicines Agency for the treatment of alcoholism. The relevant studies followed a harm-reduction, 'as needed' approach and showed a reduction in alcohol consumption with nalmefene 20 mg rather than increased abstinence rates, (which was not the primary goal of the relevant studies). The available literature is reviewed and discussed. Nalmefene appears to be a safe and effective treatment for alcohol dependence.

All-cause Mortality in Placebo-controlled Clinical Trials of Methylnaltrexone: A Pooled Analysis

Purpose: To evaluate all-cause mortality and baseline cardiovascular risk factors in patients enrolled in placebo (PBO)-controlled trials conducted with the peripheral mu-opioid antagonist, methylnaltrexone (MNTX). Methods: This analysis assessed all-cause mortality in patients enrolled in Phase 2 and Phase 3 PBO-controlled trials of MNTX for the treatment of opioid-induced constipation (advanced illness and noncancer pain patients) and postoperative ileus. The probability of death was calculated using the Cox proportional-hazards model, with a 2-sided test and significance level of 0.05, to compare the time to death for patients treated with MNTX versus PBO. Baseline cardiovascular risk factors were also assessed. Results: Overall, 3,491 patients were treated with either MNTX (n=2,413) or PBO (n=1,078). Demographic characteristics were comparable in the MNTX (33.9% ≥60 years of age, 54.7% female, 38.9% with BMI ≥30) and PBO groups (38.7% ≥ 60 years of age, 54.5% female, 36.5% with BMI ≥30). Cardiovascular history and risk factors across all patients in the analysis included: hypertension (MNTX: 44.3%, PBO: 45.5%), hyperlipidemia/hypercholesterolemia (26.2%, 23.5%), diabetes (22.3%, 23.9%), angina (11.2%, 13.2%), myocardial infarction (13.2%, 13.1%), and stroke (11.3%, 12.2%). Some subjects had multiple risk factors. There were 25 deaths (rate=13.7 events per 100 person-years of exposure) in the MNTX group and 21 deaths (rate=31.4 events per 100 person-years of exposure) in the PBO group. The hazard ratio for risk of death in the MNTX group relative to the PBO group was 0.46 (p=0.007), corresponding to a relative reduction in risk of death of 54%. Conclusion: In a pooled analysis of all-cause mortality in PBO-controlled trials of MNTX, a lower risk of mortality was observed in MNTX-treated patients. Kaplan-Meier Curve of All-Cause Mortality in Placebo-Controlled Studies with Methylnaltrexone. Disclosure - Lynn Webster: Consultant for AstraZeneca, Covidien Mallinckrodt, Nektar Therapeutics, Jazz Pharmaceuticals, CVS, Boehringer Ingelheim, Neura Therapeutik, Orexo, Quintiles, Theravance Darren Brenner: Consultant and speaker for Salix, Consultant for Perrigo, Speaker Bureau for Ironwood/Forrest Robert L. Rolleri: employee of and holds stock in Salix Pharmaceuticals, Inc. Andrew C. Barrett: employee of and holds stock in Salix Pharmaceuticals, Inc. Enoch Bortey: employee of and holds stock in Salix Pharmaceuticals, Inc. Craig Paterson: employee of and holds stock in Salix Pharmaceuticals, Inc. William P. Forbes: officer and employee of and holds stock in Salix Pharmaceuticals, Inc.Figure

Binding mode characterization of 6α- and 6β-N-heterocyclic substituted naltrexamine derivatives via docking in opioid receptor crystal structures and site-directed mutagenesis studies: Application of the ‘message–address’ concept in development of mu opioid receptor selective antagonists

Highly selective opioid receptor antagonists are essential pharmacological probes in opioid receptor structural characterization and opioid agonist functional studies. Currently, there is no highly selective, nonpeptidyl and reversible mu opioid receptor antagonist available. Among a series of naltrexamine derivatives that have been designed and synthesized, two compounds, NAP and NAQ, were previously identified as novel leads for this purpose based on their in vitro and in vivo pharmacological profiles. Both compounds displayed high binding affinity and selectivity to the mu opioid receptor. To further study the interaction of these two ligands with the three opioid receptors, the recently released opioid receptor crystal structures were employed in docking studies to further test our original hypothesis that the ligands recognize a unique ‘address’ domain in the mu opioid receptor involving Trp318 that facilitates their selectivity. These modeling results were supported by site-directed mutagenesis studies on the mu opioid receptor, where the mutants Y210A and W318A confirmed the role of the latter in binding. Such work not only enriched the ‘message–address’ concept, also facilitated our next generation ligand design and development.

The effects of alcohol on the pharmacokinetics and pharmacodynamics of the selective mu‐opioid receptor antagonist GSK1521498 in healthy subjects

The mu-opioid system has a key role in hedonic and motivational processes critical to substance addiction. However, existing mu-opioid antagonists have had limited success as anti-addiction treatments. GSK1521498 is a selective and potent mu-opioid antagonist being developed for the treatment of overeating and substance addictions. In this study, 28 healthy participants were administered single doses of GSK1521498 20 mg, ethanol 0.5 g/kg body weight, or both in combination, in a double blind placebo controlled four-way crossover design. The primary objective was to determine the risk of significant adverse pharmacodynamic and pharmacokinetic (PK) interactions. The effects of GSK1521498 on hedonic and consummatory responses to alcohol and the attentional processing of alcohol-related stimuli, and their modulation by the OPRM1 A118G polymorphism were also explored. GSK1521498 20 mg was well tolerated alone and in combination with ethanol. There were mild transient effects of GSK1521498 on alertness and mood that were greater when it was combined with ethanol. These effects were not of clinical significance. There were no effects of GSK1521498 on reaction time, hedonic or consummatory responses. These findings provide encouraging safety and PK data to support continued development of GSK1521498 for the treatment of alcohol addiction.

In Vitro and In Vivo Characterization of the Novel Opioid Antagonists NAP and NAQ

Opioid use, abuse and addiction have risen dramatically over the past few years. Opioid antagonists are used to manage acute opioid withdrawal, addiction, and peripheral side effects of opioid therapy. We have developed reversible and selective mu opioid neutral antagonists to aid in opioid overdose therapy while potentially minimizing withdrawal as compared to inverse agonists. We characterized two novel 6β‐N‐heterocyclic naltrexamine derivatives (NAP and NAQ) in mouse models of opioid‐mediated antinociception, locomotor activity, gastrointestinal transit, physical dependence and acetic acid writhing and also in an in vitro beta‐arrestin2‐GFP translocation assay. NAQ produced dose‐and time‐dependent reversal of morphine‐induced antinociception and hyperlocomotion and suppressed writhing behavior after acetic acid administration. In chronic morphine treated mice, NAQ produced modest withdrawal at higher doses that was much lower in intensity compared to equivalent doses of naloxone. NAP and NAQ antagonized DAMGO induced beta‐arrestin2 recruitment in MOR expressing cells. NAP also had a different pharmacokinetic profile, having a longer time to reach peak effect and a longer duration of action. NAP and NAQ demonstrate a unique pharmacology and may represent new and improved therapies for managing opioid overdose, addiction, and side effects associated with opioid analgesics.

KCl-induced repetitive cortical spreading depression inhibits trigeminal neuronal firing mediated by 5-HT1B/1D and opioid receptor

Results A total of 30 neurons in the TCC responsive to nociceptive activation of the dura mater were studied. A sub-poplation, 9 out of the 30, showed an average inhibition of firing of 65±14% from baseline with CSD. This inhibitory response was reversed by intravenous administration of the 5-HT1B/1D receptor antagonist, GR127935 (3mg/kg), and a mu-opioid antagonist, naloxone (1.5 mg/kg), five minutes after injection (p < 0.05). Conclusion The present findings show that repetitive CSDs inhibit a subpopulation of dural nociceptive trigeminal neurons, an effect mediated by serotonin and opioids receptors. Understanding how the cerebral cortex modulates trigeminovascular nociception will improve our understanding of the pathophysiology of migraine.