Brain Opioid System Research Articles

Cocaine Self-administration Regulates Transcription of Opioid Peptide Precursors and Opioid Receptors in Rat Caudate Putamen and Prefrontal Cortex

The brain opioid system plays an important role in cocaine reward. Altered signaling in the opioid system by chronic cocaine exposure contributes to cocaine-seeking and taking behavior. The current study investigated concurrent changes in the gene expression of multiple components in rat brain opioid system following cocaine self-administration. Animals were limited to 40 infusions (1.5 mg/kg/infusion) within 6 h per day for five consecutive days. We then examined the mRNA levels of opioid receptors including mu (Oprm), delta (Oprd), and kappa (Oprk), and their endogenous opioid peptide precursors including proopiomelanocortin (Pomc), proenkephalin (Penk), prodynorphin (Pdyn) in the dorsal striatum (CPu) and the prefrontal cortex (PFC) 18 h after the last cocaine infusion. We found that cocaine self-administration significantly increased the mRNA levels of Oprm and Oprd in both the CPu and PFC, but had no effect on Oprk mRNA levels in either brain region. Moreover, cocaine had a greater influence on the mRNA levels of opioid peptide precursors in rat CPu than in the PFC. In the CPu, cocaine self-administration significantly increased the mRNA levels of Penk and Pdyn and abolished the mRNA levels of Pomc. In the PFC, cocaine self-administration only increased Pdyn mRNA levels without changing the mRNA levels of Pomc and Penk. These data suggest that cocaine self-administration influences the expression of multiple genes in the brain opioid system, and the concurrent changes in these targets may underlie cocaine-induced reward and habitual drug-seeking behavior.

Buprenorphine prevents stress-induced blunting of nucleus accumbens dopamine response and approach behavior to food reward in mice

Alterations to the mesolimbic dopamine (DA) system are thought to underlie dysfunctional reward processing in stress-related psychiatric disorders. Using in vivio microdialysis in awake freely moving mice, we assessed the effects of stress on the motivational and neurochemical correlates underlying conditioned approach behavior for palatable food in the non-deprived mouse. Mice trained to approach and consume food in a familiar environment exhibited a 30% increase in nucleus accumbens shell (AcbSh) extracellular dopamine levels coincident with approach towards and consumption of the food reward. This effect was not observed in mice that were presented with the food in an unfamiliar environment or were exposed for the first time and were region specific. The addition of an acute environmental stressor (bright light and novel scent) during food exposure decreased DA release and delayed approach to the food. The disruptive impact of acute novelty stress on DA levels and approach behavior was reversed in animals pretreated with buprenorphine, an opioid drug with antidepressant-like and anxiolytic effects. Together, these data indicate that exposure to mild stress reduces incentive drive to approach palatable food via alterations in AcbSh dopamine responsiveness to food reward. Moreover, they implicate the brain opioid system as a potential pharmacological target for counteracting behavioral and neurochemical elements associated with stress.

Independent and Interactive Effects of OPRM1 and DAT1 Polymorphisms on Alcohol Consumption and Subjective Responses in Social Drinkers.

The current study examined independent and interactive effects of polymorphisms of the mu opioid receptor gene (OPRM1, A118G) and variable number tandem repeats of the dopamine transporter gene (DAT1, SLC6A3) on alcohol consumption and subjective responses to alcohol in 127 young, healthy, social drinkers. Participants completed an in-person assessment, which included self-reported alcohol drinking patterns and blood sampling for DNA, and in a second visit, a cumulative alcohol dosing procedure with subjective ratings across multiple time points and breath alcohol contents (0.03 to 0.1%). DNA was analyzed for OPRM1 AA versus AG/GG (*G) genotypes, DAT1 10-repeat allele (A10) versus 9 or lesser alleles (A9), and ancestral informative markers. There were significant epistatic interactions between OPRM1 and DAT1 genotypes. Subjective High Assessment Scale scores after alcohol consumption were highest in *G and A9 carriers, and lowest in *G and A10 carriers. Negative subjective effects were also highest in *G and A9 carriers. Effects were similar in a sensitivity analysis limited to Caucasian subjects. There were independent and epistatic interactions on drinking. The OPRM1 *G allele was independently associated with fewer heavy drinking days. The A9 allele was associated with a greater number of drinking days, which was attenuated in carriers of the *G allele. These findings highlight the biological importance of interactions between these 2 genes and interactions between brain opioid and dopamine systems.

The psychoneuroendocrine-immunotherapy of cancer: Historical evolution and clinical results.

The prognosis of the neoplastic diseases depends not only on the biogenetic characteristics of cancer cells but also on the immunological response of patients, which may influence the biological features of cancer cells themselves as well as the angiogenic processes. Moreover, the immune system in vivo is under a physiological psychoneuroendocrine (PNE) regulation, mainly mediated by the brain opioid system and the pineal gland. In more detail, the anticancer immunity is stimulated by the pineal hormone melatonin (MLT) and inhibited by the opioid system, namely, through a mu-opioid receptor. Several alterations involving the pineal endocrine function and the opioid system have been described in cancer patients, which could play a role in tumor progression itself. Therefore, the pharmacological correction of cancer progression-related anomalies could contribute to control cancer diffusion, namely, the pineal endocrine deficiency and the hyperactivity of brain opioid system. In fact, the administration of pharmacological doses of the only MLT has already been proven to prolong the 1-year survival in untreatable metastatic cancer patients. Better results may be achieved by associating other pineal indoles to MLT, mu-opioid antagonists, cannabinoids, beta-carbolines. Moreover, these neuroendocrine combinations may be successfully associated with antitumor cytokines, such as interleukin (IL)-2 and IL-12, as a PNE-immune cancer therapy as well as with antitumor plants as PNE-phytotherapy of cancer in an attempt to propose possible anticancer treatments also to patients with disseminated cancer and untreatable according to the standard oncology.

Acute naltrexone does not remediate fronto-striatal disturbances in alcoholic and alcoholic polysubstance-dependent populations during a monetary incentive delay task.

There is a concerted research effort to investigate brain mechanisms underlying addiction processes that may predicate the development of new compounds for treating addiction. One target is the brain's opioid system, because of its role in the reinforcing effects of substances of abuse. Substance-dependent populations have increased numbers of the mu opioid receptor (MOR) in fronto-striatal regions that predict drug relapse, and demonstrate disturbances in these regions during the processing of non-drug rewards. Naltrexone is currently licensed for alcohol and opiate dependence, and may remediate such disturbances through the blockade of MORs in fronto-striatal reward circuitry. Therefore, we examined the potential acute modulating effects of naltrexone on the anticipation of, and instrumental responding for, non-drug rewards in long-term abstinent alcoholics, alcoholic poly substance-dependent individuals and controls using a monetary incentive delay (MID) task during a randomized double blind placebo controlled functional MRI study. We report that the alcoholic poly substance-dependent group exhibited slower and less accurate instrumental responding compared to alcoholics and controls that was less evident after acute naltrexone treatment. However, naltrexone treatment was unable to remediate disturbances within fronto-striatal regions during reward anticipation and 'missed' rewards in either substance-dependent group. While we have not been able to identify the underlying neural mechanisms for improvement observed with naltrexone in the alcoholic poly-substance dependent group, we can confirm that both substance-dependent groups exhibit substantial neural deficits during an MID task, despite being in long-term abstinence.

5-HT2A Serotonin Receptor Density in Adult Male Rats' Hippocampus after Morphine-based Conditioned Place Preference.

Introduction:A close interaction exists between the brain opioid and serotonin (5-HT) neurotransmitter systems. Brain neurotransmitter 5-HT plays an important role in the regulation of reward-related processing. However, a few studies have investigated the potential role of 5-HT2A receptors in this behavior. Therefore, the aim of the present study was to assess the influence of morphine and Conditioned Place Preference (CPP) on the density of 5-HT2A receptor in neurons of rat hippocampal formation.Methods:Morphine (10 mg/kg, IP) was injected in male Wistar rats for 7 consecutive days (intervention group), but control rats received just normal saline (1 mL/kg, IP). We used a hotplate test of analgesia to assess induction of tolerance to analgesic effects of morphine on days 1 and 8 of injections. Later, two groups of rats were sacrificed one day after 7 days of injections, their whole brains removed, and the striatum and PFC immediately dissected. Then, the NR1 gene expression was examined with a semi-quantitative RT-PCR method.Results:Our data showed that the maximum response was obtained with 2.5 mg/kg of morphine. The density of 5-HT2A receptor in different areas of the hippocampus increased significantly at sham-morphine and CPP groups (P<0.05). On the other hand, the CPP groups had more 5-HT2A receptors than sham-morphine groups and also the sham-morphine groups had more 5-HT2A receptors than the control groups.Conclusion:We concluded that the phenomenon of conditioned place preference induced by morphine can cause a significant increase in the number of serotonin 5-HT2A receptors in neurons of all areas of hippocampus.

P-79AN FMRI STUDY OF NALMEFENE ON ALCOHOL EFFECTS IN REWARD ANTICIPATION IN ALCOHOL DEPENDENCE

Alcohol dependence is a brain disease with a progressive, and relapsing, course. Alcohol is directly and indirectly affecting many neurochemical brain systems, leading to dysregulations for example in the brain opioid systems. Functional neuroimaging allows studying individuals with alcohol dependence directly and has contributed greatly …

S.03.03 5-HT1A receptors in depressed patients: Evidence from PET, post mortem and EEG based studies

The Sweet Taste Test (STT) is a standardized measure designed to index the ability to detect differences in sweet tastes (sweet taste sensitivity) and hedonic responses to sweet tastes (sweet taste liking). Profiles of response on the STT suggest enhanced hedonic responses to sweet tastes in psychiatric disorders characterized by dysfunctional reward processing systems, including binge-eating disorders and substance use disorders, and a putative mechanism governing STT responses is the brain opioid system. The present study examined STT responses in 20 adults with autism spectrum disorder (ASD) and 38 healthy control adults. There were no differences in sweet taste sensitivity or hedonic response to sweet tastes between the ASD and control groups. Within the ASD sample, ASD symptom severity was associated with sweet taste sensitivity, but not hedonic response to sweet taste. Results may ultimately shed light on brain opioid system functioning in ASD.

Predisposing effects of neonatal visceral pain on abuse-related effects of morphine in adult male Sprague Dawley rats.

Adverse early life experiences are risk factors for drug abuse and addiction. Changes in brain opioid systems have been demonstrated in response to neonatal visceral pain (NVP), but the impact of these changes on abuse-related effects of morphine are unknown. The NVP procedure used models chronic visceral hyperalgesia persisting across development. Intravenous self-administration, drug discrimination, and locomotor activity were used to compare the abuse-related effects of morphine in NVP and control rats. Rats self-administered 0.3mg/kg/inj morphine under an FR1 schedule, and dose-effect functions for morphine were then established. Separate rats were trained to discriminate 3.2mg/kg morphine from saline under an FR20 schedule, and morphine dose-effect functions were then determined in the absence and presence of 0.1mg/kg naltrexone. A third group of rats was tested with a range of morphine doses in an assay of locomotor activity, then injected daily with 10mg/kg morphine to assess locomotor sensitization. NVP rats self-administered more morphine than controls at reinforcing doses. Discriminative stimulus effects of morphine were similar between groups, but in the presence of naltrexone, the ED50 for morphine was more than 12× greater in control rats than in NVP animals. Morphine did not stimulate locomotor activity at any tested dose in NVP rats, although significant effects were observed in controls. Finally, significant locomotor sensitization was observed only in NVP rats. NVP-induced changes in brain opioid systems have persistent pharmacological consequences into adulthood and may increase sensitivity to abuse-related effects of opioids across development.

Neuroimaging of human brain opioid system

Les recepteurs opioides, dont la presence etait suspectee depuis longtemps, ont pu etre mis en evidence avec leurs ligands dans les annees 1970 grâce a des etudes experimentales in vitro. Ce n’est que vers 1985 que leur etude in vivo chez l’Homme a ete possible avec l’avenement de la tomographie par emission de positons (TEP). Depuis, de multiples etudes TEP ont permis de clarifier la physiologie et la pathologie du systeme opioide endogene humain dans de multiples conditions et pathologies. Ainsi, les etudes d’activation en douleur experimentale tonique ont montre une activation du systeme opioide au niveau de l’amygdale ipsilaterale a la douleur, du thalamus medial et lateral, du cortex insulaire et de l’hypothalamus controlateraux a la douleur, et enfin dans le gyrus cingulaire anterieur et le cortex prefrontal bilateralement. Cette activation est correlee negativement avec la perception douloureuse. Ces etudes d’activation ont egalement montre une activation differentielle dont l’importance et le sens varient en fonction du sexe. En matiere de douleur nociceptive, il existe vraisemblablement une secretion accrue et reactionnelle d’opioides endogenes comme en temoigne la baisse de la fixation du radioligand aux recepteurs chez les patients atteints d’une pathologie douloureuse inflammatoire chronique (e.g. le rhumatisme inflammatoire). En matiere de douleurs neuropathiques (DN), il existe egalement une secretion accrue d’opioides endogenes reactionnelle a la douleur. En outre, les recepteurs opioides encephaliques sont relativement epargnes dans le type peripherique des DN, alors qu’il semble exister une perte de ces recepteurs, lateralisee a l’hemisphere ou siege la lesion causale de la douleur (controlateral a la douleur clinique), et se localisant au niveau du systeme nociceptif medial dans le type central des DN. Cette difference du profil du systeme opioide entre douleurs peripheriques et centrales explique probablement leur sensibilite differentielle aux morphiniques exogenes, relativement plus efficaces dans les douleurs neuropathiques peripheriques. La stimulation du cortex moteur a visee antalgique, utilisee en dernier recours dans le traitement des douleurs neuropathiques refractaires au traitement medical, induit une secretion d’opioides endogenes dans certaines structures cles du systeme opioide endogene, ce qui peut devoiler un des mecanismes d’action de cette procedure. Un examen TEP preoperatoire a la diprenorphine pourrait constituer un test predictif de la reponse des DN a la stimulation du cortex moteur. Ces etudes realisees jusqu’a present ouvrent de multiples perspectives afin de clarifier le role de ce systeme dans de multiples pathologies du systeme nerveux.

Intact hedonic responses to sweet tastes in autism spectrum disorder

The Sweet Taste Test (STT) is a standardized measure designed to index the ability to detect differences in sweet tastes (sweet taste sensitivity) and hedonic responses to sweet tastes (sweet taste liking). Profiles of response on the STT suggest enhanced hedonic responses to sweet tastes in psychiatric disorders characterized by dysfunctional reward processing systems, including binge-eating disorders and substance use disorders, and a putative mechanism governing STT responses is the brain opioid system. The present study examined STT responses in 20 adults with autism spectrum disorder (ASD) and 38 healthy control adults. There were no differences in sweet taste sensitivity or hedonic response to sweet tastes between the ASD and control groups. Within the ASD sample, ASD symptom severity was associated with sweet taste sensitivity, but not hedonic response to sweet taste. Results may ultimately shed light on brain opioid system functioning in ASD.

The role of the opioid system in alcohol dependence

The role of the brain opioid system in alcohol dependence has been the subject of much research for over 25 years. This review explores the evidence: firstly describing the opioid receptors in terms of their individual subtypes, neuroanatomy, neurophysiology and ligands; secondly, summarising emerging data from specific neurochemical, behavioural and neuroimaging studies, explaining the characteristics of addiction with a focus on alcohol dependence and connecting the opioid system with alcohol dependence; and finally reviewing the known literature regarding opioid antagonists in clinical use for alcohol dependence. Further interrogation of how modulation of the opioid system, via use of MOP (mu), DOP (delta) and KOP (kappa) agents, restores the balance of a dysregulated system in alcohol dependence should increase our insight into this disease process and therefore guide better methods for understanding and treating alcohol dependence in the future.

Effects of amphetamine on the human brain opioid system – a positron emission tomography study

Studies in rodents have shown that psychostimulant drugs such as cocaine and amphetamine cause endorphin release in the brain reward system. There is also evidence for the involvement of the opioid system in human psychostimulant dependence. The acute effects of an i.v. psychostimulant drug on the brain opioid system, however, have not yet been investigated in humans. We hypothesized that an i.v. dose of amphetamine as compared to placebo would cause an opioid release in the human brain reward system, measurable as a reduction of the binding potential of the μ-opioid receptor radioligand [(11)C]carfentanil. Ten healthy young men were examined using positron emission tomography (PET) and [(11)C]carfentanil in three sessions: at baseline; after placebo; after an i.v. amphetamine dose of 0.3 mg/kg bodyweight. The order of amphetamine and placebo was double-blinded and randomized. PET examinations were performed with a Siemens high resolution research tomograph. Data were analysed with the simplified reference tissue model, applying manually drawn regions of interest for every subject. Using repeated measures analysis of variance, we found no significant differences in [(11)C]carfentanil binding potential between amphetamine and placebo conditions in any of the investigated brain regions. In contrast to data from rodent studies and a recent study of oral amphetamine administration in humans, an i.v. dose of amphetamine does not cause any acute opioid release in healthy human subjects. The postulated role of the opioid system in mediating the effects of amphetamine needs to be further investigated in animal models of the disease as well as in patient populations.

Effects of neonatal visceral pain on morphine tolerance, dependence, and withdrawal in rats

Changes in brain opioid systems have been demonstrated in response to neonatal visceral pain (NVP), but few studies have examined the impact of these changes on opioid pharmacology. In these studies, we examined the effects of NVP on the development of tolerance, dependence, and expression of withdrawal effects of morphine in the rat. Experimental rats were subjected to a colorectal distension procedure on postnatal days 4, 6, and 8 to induce NVP, while control rats were not exposed to the NVP procedure. All rats were gradually shaped to a terminal FR20 schedule reinforced by food presentation. Once responding was stable and reliable, saline was injected subcutaneously (SC) before behavioral sessions, and morphine was administered (SC) immediately after behavioral sessions. Morphine doses were increased one quarter‐log every 7 days, from 1.0 mg/kg, to a final dose of 30 mg/kg, upon which rats were maintained for the duration of the experiment. Various doses of the opioid antagonist naltrexone (NTX) were sometimes administered 10 min before behavioral sessions to precipitate withdrawal. For both groups of rats, NTX dose‐dependently suppressed response rates, indicative of a precipitated withdrawal effect on food‐maintained responding. However, NTX induced more pronounced rate suppression in NVP rats at all tested doses. These findings demonstrate that the changes in brain opioid systems elicited by NVP have persistent pharmacological consequences into adulthood, are consistent with our previous studies suggesting that NVP increases sensitivity to abuse‐related effects of opioids across development, and extend our characterization of this vulnerable phenotype to include an increased susceptibility to antagonist‐precipitated withdrawal. These studies supported by the UAMS Center for Translational Neuroscience (RR020146) and the UAMS Translational Research Institute (RR029884).

Naltrexone Modification of Drinking Effects in a Subacute Treatment and Bar‐Lab Paradigm: Influence of OPRM1 and Dopamine Transporter (SLC6A3) Genes

Naltrexone is moderately effective for the treatment of alcohol dependence, but there is great individual variability. The opioid receptor (OPRM1) single nucleotide polymorphism (SNP) asn40asp has been shown to alter alcohol and naltrexone response in animals and humans. In addition, the brain opioid and dopamine systems interact and might underlie drinking and craving. This study investigated the effects of the OPRM1 SNP and dopamine transporter (DAT) variable number of tandem repeat (VNTR) genetic differences on drinking, alcohol effects, and naltrexone response under controlled conditions in nontreatment-seeking alcoholics. Two hundred and sixty-five nontreatment-seeking individuals with alcohol dependence were genotyped a priori for the OPRM1 asn40asp SNP and post hoc for DAT (SLC6A3) 9 and 10 VNTRs. Asp40 carriers (n=43) and matched asn40 homozygotes (n=40) were randomized to naltrexone or placebo for 7days before receiving a priming drink and limited-access alcohol consumption in a bar-lab setting. Effects of genotypes on natural drinking as well as drinking, alcohol effects, and response to naltrexone in the bar-lab setting were examined by genotype. There were no significant main effects of naltrexone or OPRM1 genotype, or any medication by OPRM1 interaction, on drinking variables. However, in individuals who had at least one DAT 9 VNTR, and who were also OPRM1 asn40 homozygotes, naltrexone reduced drinks/d consumed under natural conditions (p=0.006), but not in the bar-lab. OPRM1 asn40 homozygotes (p=0.028) and DAT 9 VNTR carriers (p=0.032) had more stimulation to alcohol after the priming drink. This study does not support a salient role for the OPRM1 asp40 alone in predicting drinking or naltrexone effects. However, although exploratory and in need of replication, it introduces the possibility that epistasis between the OPRM1 gene and DAT gene might need to be taken into account when examining differential genetic response to alcohol or medication treatment, especially in early-stage alcoholics.

Persistent behavioral impairments and alterations of brain dopamine system after early postnatal administration of thimerosal in rats

The neurotoxic organomercurial thimerosal (THIM), used for decades as vaccine preservative, is a suspected factor in the pathogenesis of some neurodevelopmental disorders. Previously we showed that neonatal administration of THIM at doses equivalent to those used in infant vaccines or higher, causes lasting alterations in the brain opioid system in rats. Here we investigated neonatal treatment with THIM (at doses 12, 240, 1440 and 3000 μg Hg/kg) on behaviors, which are characteristically altered in autism, such as locomotor activity, anxiety, social interactions, spatial learning, and on the brain dopaminergic system in Wistar rats of both sexes. Adult male and female rats, which were exposed to the entire range of THIM doses during the early postnatal life, manifested impairments of locomotor activity and increased anxiety/neophobia in the open field test. In animals of both sexes treated with the highest THIM dose, the frequency of prosocial interactions was reduced, while the frequency of asocial/antisocial interactions was increased in males, but decreased in females. Neonatal THIM treatment did not significantly affect spatial learning and memory. THIM-exposed rats also manifested reduced haloperidol-induced catalepsy, accompanied by a marked decline in the density of striatal D 2 receptors, measured by immunohistochemical staining, suggesting alterations to the brain dopaminergic system. Males were more sensitive than females to some neurodisruptive/neurotoxic actions of THIM. These data document that early postnatal THIM administration causes lasting neurobehavioral impairments and neurochemical alterations in the brain, dependent on dose and sex. If similar changes occur in THIM/mercurial-exposed children, they could contribute do neurodevelopmental disorders.

P.4.007 The effect of changes in the brain opioid system activity on the adaptive behavior of BALB/c and C57BL/6 mice

P.4.007 The effect of changes in the brain opioid system activity on the adaptive behavior of BALB/c and C57BL/6 mice

Role of the Brain Dopaminergic and Opioid System in the Regulation of “Child’s” (Maternal Bonding) Behavior of Newborn Albino Rats

Administration of D(2) receptor antagonist clebopride in a dose not affecting locomotor activity was followed by a decrease in maternal bonding behavior of 10-day-old and 15-day-old albino rat pups. D(1) receptor antagonist SCH23390 had a stimulatory effect only on the behavior of 10-day-old newborns. Opioid peptide β-casomorphin-7 abolished the effect of clebopride in rat pups of the older age group.

The Brain Dynorphins/Kappa Opioid Receptor (DYN/KOPR) System Plays a Role in Anxiety Regulation

Our current understanding of the biological basis of anxiety is limited. Research on affective states including anxiety has focused on the roles of the brain gama-aminobutyric acid (GABA) and monoamine (e.g., serotonin, dopamine, norepi-nephrine) systems. The brain opioid systems have been implicated in the regulation of emotion. In this review, we will focus on the role of dynorphins/kappa opioid receptor (DYN/KOPR) system in anxiety regulation. Recent preclinical research suggests that KOPR antagonists have anxiolytic effects. Together with the roles of this brain system in depression and drug addiction, KOPR is a potential target for new medications.

Interaction of supraspinally administered interferon-alpha with opioid system in the production of antinociception

We examined the antinociceptive effect of intracerebroventricularly (i.c.v.) or intrathecally (i.t.) administered of interferon-alpha (IFN-alpha) using the tail-flick analgesic test in mice. IFN-alpha administered i.c.v. but not i.t. showed an antinociceptive effect in a dose-dependent manner (0.05-5 microg). To examine the possible interaction with brain opioid system, IFN-alpha was cotreated with either beta-endorphin or morphine. Combined i.c.v. treatment of IFN-alpha (0.5 microg) with beta-endorphin (0.125 microg) caused a synergistic antinociceptive effect. And also, the synergistic interaction maintained at least for 60 min after the co-treatment of IFN-alpha and beta-endorphin. However, the combined treatment of i.t. IFN-alpha with i.c.v. beta-endorphin showed neither an additive nor a synergistic antinociceptive profile. The i.c.v. co-treatment of IFN-alpha with morphine (0.2 microg) showed an additive antinociceptive effect only. The i.t. administered IFN-alpha did not show any additive antinociceptive effect when morphine was administered i.c.v. simultaneously. Taken together, our results suggest that supraspinally co-administered IFN-alpha and beta-endorphin may produce antinociception synergistically via interaction of IFN-alpha with supraspinal beta-endorphin sensitive opioid receptors.