Repeated loss of the ability of a wild pepper disease resistance gene to function at high temperatures suggests that thermoresistance is a costly trait.

Specificity in plant-pathogen gene-for-gene (GFG) interactions is determined by the recognition of pathogen proteins by the products of plant resistance (R) genes. The evolutionary dynamics of R genes in plant-virus systems is poorly understood. We analyse the evolution of the L resistance locus to tobamoviruses in the wild pepper Capsicum annuum var. glabriusculum (chiltepin), a crop relative undergoing incipient domestication. The frequency, and the genetic and phenotypic diversity, of the L locus was analysed in 41 chiltepin populations under different levels of human management over its distribution range in Mexico. The frequency of resistance was lower in Cultivated than in Wild populations. L-locus genetic diversity showed a strong spatial structure with no isolation-by-distance pattern, suggesting environment-specific selection, possibly associated with infection by the highly virulent tobamoviruses found in the surveyed regions. L alleles differed in recognition specificity and in the expression of resistance at different temperatures, broad-spectrum recognition of P0 + P1 pathotypes and expression above 32°C being ancestral traits that were repeatedly lost along L-locus evolution. Overall, loss of resistance co-occurs with incipient domestication and broad-spectrum resistance expressed at high temperatures has apparent fitness costs. These findings contribute to understand the role of fitness trade-offs in plant-virus coevolution.

Tobacco Mild Green Mosaic Virus (TMGMV) Isolates from Different Plant Families Show No Evidence of Differential Adaptation to Their Host of Origin.

The relevance of tobamoviruses to crop production is increasing due to new emergences, which cannot be understood without knowledge of the tobamovirus host range and host specificity. Recent analyses of tobamovirus occurrence in different plant communities have shown unsuspectedly large host ranges. This was the case of the tobacco mild green mosaic virus (TMGMV), which previously was most associated with solanaceous hosts. We addressed two hypotheses concerning TMGMV host range evolution: (i) ecological fitting, rather than genome evolution, determines TMGMV host range, and (ii) isolates are adapted to the host of origin. We obtained TMGMV isolates from non-solanaceous hosts and we tested the capacity of genetically closely related TMGMV isolates from three host families to infect and multiply in 10 hosts of six families. All isolates systemically infected all hosts, with clear disease symptoms apparent only in solanaceous hosts. TMGMV multiplication depended on the assayed host but not on the isolate's host of origin, with all isolates accumulating to the highest levels in Nicotiana tabacum. Thus, results support that TMGMV isolates are adapted to hosts in the genus Nicotiana, consistent with a well-known old virus-host association. In addition, phenotypic plasticity allows Nicotiana-adapted TMGMV genotypes to infect a large range of hosts, as encountered according to plant community composition and transmission dynamics.

Evidence for the existence of facilitatory interactions between the dopamine D2 receptor and the oxytocin receptor in the amygdala of the rat. Relevance for anxiolytic actions.

Introduction: The amygdala is a limbic region of high value for understanding anxiety and its treatment. Dopamine D2 receptors (D2Rs) and oxytocin receptors (OXTRs) have both been shown to participate in modulating anxiety involving effects in the amygdala. The goal is to understand if D2R-OXTR heterocomplexes exist in the central amygdala and if, through enhancing allosteric receptor-receptor interactions, may enhance anxiolytic actions. Methods: The methods used involve the shock-probe burying test, the in situ proximity ligation assay (PLA), image acquisition and analysis, and the BRET2 assay. Bilateral cannulas were introduced into the amygdala, and the effects of the coadministration of oxytocin and the D2R-like agonist quinpirole into the amygdala were studied. Results: The combination treatment enhanced the anxiolytic effects compared to the single treatment. The D2R/D3R antagonist raclopride blocked the effects of the combination treatment of oxytocin and the D2R agonist, although oxytocin is regarded as a distinct modulator of fear-mediating anxiolytic effects. In situ PLA results indicate the existence of D2R-OXTR heteroreceptor complexes and/or the co-location of OXTR and D2R within the same cell membrane nanodomains in the central amygdala. With BRET2, evidence is given for the existence of D2R-OXTR heteromers in HEK293 cells upon co-transfection. Discussion: The enhanced behavioral effects observed upon co-treatment with OXTR and D2R agonists may reflect the existence of improved positive receptor-receptor interactions in the putative D2R-OXTR heterocomplexes in certain neuronal populations of the basolateral and central amygdala. The D2R-OXTR heterocomplex, especially upon agonist co-activation in the central amygdala, may open a new pharmacological venue for the treatment of anxiety.

Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Intravenous Infusions of PF-07304814 (Lufotrelvir) in Participants Hospitalized With COVID-19.

Background: An urgent need remains for antiviral therapies to treat patients hospitalized with COVID-19. PF-07304814-the prodrug (lufotrelvir) and its active moiety (PF-00835231)-is a potent inhibitor of the SARS-CoV-2 3CL protease. Method: Eligible participants were 18 to 79 years old and hospitalized with confirmed COVID-19. This first-in-human phase 1b study was designed with 2 groups: single ascending dose (SAD) and multiple ascending dose (MAD). Participants could receive local standard-of-care therapy. In SAD, participants were randomized to receive a 24-hour infusion of lufotrelvir/placebo. In MAD, participants were randomized to receive a 120-hour infusion of lufotrelvir/placebo. The primary endpoint was to assess the safety and tolerability of lufotrelvir. The secondary endpoint was to evaluate the pharmacokinetics of lufotrelvir and PF-00835231. Results: In SAD, participants were randomized to receive 250 mg lufotrelvir (n = 2), 500 mg lufotrelvir (n = 2), or placebo (n = 4) by continuous 24-hour infusion. In MAD, participants were randomized to receive 250 mg lufotrelvir (n = 7), 500 mg lufotrelvir (n = 6), or placebo (n = 4) by continuous 120-hour infusion. No adverse events or serious adverse events were considered related to lufotrelvir. At doses of 250 and 500 mg, concentrations for the prodrug lufotrelvir and active moiety PF-00835231 increased in a dose-related manner. Unbound concentrations of the lufotrelvir active metabolite reached steady state approximately 2- and 4-fold that of in vitro EC90 following 250- and 500-mg doses, respectively. Conclusions: These safety and pharmacokinetic findings support the continued evaluation of lufotrelvir in clinical studies. Clinical Trials Registration. ClinicalTrials.gov NCT04535167.

CB1R chronic intermittent pharmacological activation facilitates amphetamine seeking and self-administration and changes in CB1R/CRFR1 expression in the amygdala and nucleus accumbens in rats.

Patterns of drug ingestion may have a dissimilar impact on the brain, and therefore also the development of drug addiction. One pattern is binge intoxication that refers to the ingestion of a high amount of drug on a single occasion followed by an abstinence period of variable duration. In this study, our goal was to contrast the effect of continuous low amounts with intermittent higher amounts of Arachidonyl-chloro-ethylamide (ACEA), a CB1R agonist, on amphetamine seeking and ingestion, and describe the effects on the expression of CB1R and CRFR1 in the central nucleus of the amygdala (CeA) and in the nucleus accumbens shell (NAcS). Adult male Wistar rats were treated with a daily administration of vehicle or 20 µg of ACEA, or four days of vehicle followed by 100 µg of ACEA on the fifth day, for a total of 30 days. Upon completion of this treatment, the CB1R and CRFR1 expression in the CeA and NAcS was evaluated by immunofluorescence. Additional groups of rats were evaluated for their anxiety levels (elevated plus maze, EPM), amphetamine (AMPH) self-administration (ASA) and breakpoint (A-BP), as well as AMPH-induced conditioned place preference (A-CPP). Results indicated that ACEA induced changes in the CB1R and CRFR1 expression in both the NAcS and CeA. An increase in anxiety-like behavior, ASA, A-BP and A-CPP was also observed. Since the intermittent administration of 100 µg of ACEA induced the most evident changes in most of the parameters studied, we concluded that binge-like ingestion of drugs induces changes in the brain that may make the subject more vulnerable to developing drug addiction.

Assessing the Virologic Impact of Archived Resistance in the Dolutegravir/Lamivudine 2-Drug Regimen HIV-1 Switch Study TANGO through Week 144.

The TANGO study (ClinicalTrials.gov, NCT03446573) demonstrated that switching to dolutegravir/lamivudine (DTG/3TC) was non-inferior to continuing tenofovir alafenamide-based regimens (TBR) through week 144. Retrospective baseline proviral DNA genotypes were performed for 734 participants (post-hoc analysis) to assess the impact of archived, pre-existing drug resistance on 144-week virologic outcomes by last on-treatment viral load (VL) and Snapshot. A total of 320 (86%) participants on DTG/3TC and 318 (85%) on TBR had both proviral genotype data and ≥1 on-treatment post-baseline VL results and were defined as the proviral DNA resistance analysis population. Archived International AIDS Society-USA major nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, protease inhibitor, and integrase strand transfer inhibitor resistance-associated mutations (RAMs) were observed in 42 (7%), 90 (14%), 42 (7%), and 11 (2%) participants, respectively, across both groups; 469 (74%) had no major RAMs at baseline. M184V/I (1%), K65N/R (<1%), and thymidine analogue mutations (2%) were infrequent. Through week 144, >99% of participants on DTG/3TC and 99% on TBR were virologically suppressed (last on-treatment VL <50 copies/mL) regardless of the presence of major RAMs. Results from the sensitivity analysis by Snapshot were consistent with the last available on-treatment VL. In TANGO, archived, pre-existing major RAMs did not impact virologic outcomes through week 144.

GPR55 activation prevents amphetamine-induced conditioned place preference and decrease the amphetamine-stimulated inflammatory response in the ventral hippocampus in male rats.

Inflammatory response in the Central Nervous System (CNS) induced by psychostimulants seems to be a crucial factor in the development and maintenance of drug addiction. The ventral hippocampus (vHp) is part of the reward system involved in substance addiction and expresses abundant G protein-coupled receptor 55 (GPR55). This receptor modulates the inflammatory response in vitro and in vivo, but there is no information regarding its anti-inflammatory effects and its impact on psychostimulant consumption. The aim of the present study was to investigate whether vHp GPR55 activation prevents both the inflammatory response induced by amphetamine (AMPH) in the vHp and the AMPH-induced conditioned place preference (A-CPP). Wistar adult male rats with a bilateral cannula into the vHp or intact males were subjected to A-CPP (5 mg/kg). Upon the completion of A-CPP, the vHp was dissected to evaluate IL-1ß and IL-6 expression through RT-PCR, Western blot and immunofluorescence. Our results reveal that AMPH induces both A-CPP and an increase of IL-1ß and IL-6 in the vHp. The GPR55 agonist lysophosphatidylinositol (LPI, 10 µM) infused into the vHp prevented A-CPP and the AMPH-induced IL-1ß increase. CID 16020046 (CID, 10 µM), a selective GPR55 antagonist, abolished LPI effects. To evaluate the effect of the inflammatory response, lipopolysaccharide (LPS, 5 µg/µl) was infused bilaterally into the vHp during A-CPP acquisition. LPS strengthened A-CPP and increased IL-1ß/IL-6 mRNA and protein levels in the vHp. LPS also increased CD68, Iba1, GFAP and vimentin expression. All LPS-induced effects were blocked by LPI. Our results suggest that GPR55 activation in the vHp prevents A-CPP while decreasing the local neuro-inflammatory response. These findings indicate that vHp GPR55 is a crucial factor in preventing the rewarding effects of AMPH due to its capacity to interfere with proinflammatory responses in the vHp.

Dominance status is associated with a variation in cannabinoid receptor 1 expression and amphetamine reward.

The rewarding effects of psychostimulants appear to be distinct between dominant and subordinate individuals. In turn, the endocannabinoid system is an important modulator of drug reward in the nucleus accumbens and medial prefrontal cortex, however the connection with social dominance is yet to be established. Male rats were classified as dominant or subordinate on the basis of their spontaneous agonistic interactions and drug reward was assessed by means of conditioned place preference with amphetamine (AMPH). In addition, the expression of CB1R, CB2R, FAAH1, and DAGLa was quantified from accumbal and cortical tissue samples. Our findings demonstrate that dominant rats required a lesser dose of AMPH to acquire a preference for the drug-associated compartment, thereby suggesting a higher sensitivity to the rewarding effects of AMPH. Furthermore, dominants exhibited a lower expression of CB1R in the medial prefrontal cortex and nucleus accumbens. This study illustrates how CBR1 expression could differentiate the behavioral phenotypes associated to social dominance.

Dysfunctional Heteroreceptor Complexes as Novel Targets for the Treatment of Major Depressive and Anxiety Disorders.

Among mental diseases, major depressive disorder (MDD) and anxiety deserve a special place due to their high prevalence and their negative impact both on society and patients suffering from these disorders. Consequently, the development of novel strategies designed to treat them quickly and efficiently, without or at least having limited side effects, is considered a highly important goal. Growing evidence indicates that emerging properties are developed on recognition, trafficking, and signaling of G-protein coupled receptors (GPCRs) upon their heteromerization with other types of GPCRs, receptor tyrosine kinases, and ionotropic receptors such as N-methyl-D-aspartate (NMDA) receptors. Therefore, to develop new treatments for MDD and anxiety, it will be important to identify the most vulnerable heteroreceptor complexes involved in MDD and anxiety. This review focuses on how GPCRs, especially serotonin, dopamine, galanin, and opioid heteroreceptor complexes, modulate synaptic and volume transmission in the limbic networks of the brain. We attempt to provide information showing how these emerging concepts can contribute to finding new ways to treat both MDD and anxiety disorders.

Ecological risk assessment of the effects of neonicotinoid insecticides on northern bobwhites (Colinus virginianus) in the South Texas Plains Ecoregion.

Neonicotinoid insecticides are among the latest class of insecticides that can have harmful effects on birds. Approximately 30 000 kg of neonicotinoid insecticides are applied annually to 429 100 ha of row-crop fields within the South Texas Plains Ecoregion, Texas, USA. Various studies have demonstrated that treated seeds can be highly toxic to northern bobwhites, with the consumption of only 20 corn seeds causing a fatality. Similarly, other studies have indicated that neonicotinoid insecticides can reduce arthropod populations-a substantial prey base for northern bobwhites, especially during the breeding season-by approximately 60%. Our objective was to conduct an ecological risk assessment of neonicotinoid insecticides' impact on northern bobwhite (Colinus virginianus) populations in the South Texas Plains Ecoregion. We estimated that juvenile and adult northern bobwhites could intake from 7.32 to 27.0 mg/kg/day and from 10.0 to 37.5 mg/kg/day of neonicotinoid insecticides, respectively, which can cause adverse effects on growth, reproductive output, and long-term survival. Our study determined that the application of 30 000 kg of neonicotinoid insecticides annually in the South Texas Plains Ecoregion harms the region's northern bobwhite that are exposed to neonicotinoids. Integr Environ Assess Manag 2022;18:488-499. © 2021 SETAC.

Histiocytoid Sweet Syndrome associated with anorectal lymphogranuloma venereum in a patient with HIV infection.

Sweet Syndrome belongs to a group of diseases known as neutrophilic dermatoses. An uncommon variant named Histiocytoid Sweet Syndrome (HSS) can be associated with a variety of conditions, including cancer, infections, drug toxicity and others. Here we present an instance of HSS in an HIV-positive patient in an infectious disease setting.

The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: potential relevance for brain and behavior.

In the last 10 years, it has become increasingly clear that large numbers of axon collaterals extend from the oxytocin (OXT) hypothalamic axons, especially the parvocellular components, to other brain regions. Consequently, the OXT signaling system forms, like other monoamine axons, a rich functional network across several brain regions. In this manuscript, we review the recently indicated higher order G-protein coupled heteroreceptor complexes of the oxytocin receptor (OXTR), and how these, via allosteric receptor-receptor interactions modulate the recognition, signaling, and trafficking of the participating receptor protomers and their potential impact for brain and behavior. The major focus will be on complexes of the OXTR protomer with the dopamine D2 receptor (D2R) protomer and the serotonin 2A (5-HT2AR) and 2C (5-HT2CR) receptor protomers. Specifically, the existence of D2R-OXTR heterocomplexes in the nucleus accumbens and the caudate putamen of rats has led to a postulated function for this heteromer in social behavior. Next, a physical interaction between OXTRs and the growth hormone secretagogue or ghrelin receptor (GHS-R1a) was demonstrated, which consequently was able to attenuate OXTR-mediated Gαq signaling. This highlights the potential of ghrelin-targeted therapies to modulate oxytocinergic signaling with relevance for appetite regulation, anxiety, depression, and schizophrenia. Similarly, evidence for 5-HT2AR-OXTR heteromerization in the pyramidal cell layer of CA2 and CA3 in the dorsal hippocampus and in the nucleus accumbens shell was demonstrated. This complex may offer new strategies for the treatment of both mental disease and social behavior. Finally, the 5-HT2CR-OXTR heterocomplexes were demonstrated in the CA1, CA2, and CA3 regions of the dorsal hippocampus. Future work should be done to investigate the precise functional consequence of region-specific OXTR heteromerization in the brain, as well across the periphery, and whether the integration of neuronal signals in the brain may also involve higher order OXTR-GHS-R1a heteroreceptor complexes including the dopamine (DA), noradrenaline (NA) or serotonin (5-HT) receptor protomers or other types of G-protein coupled receptors (GPCRs).

Bioaccumulation of PCBs and PBDEs in Fish from a Tropical Lake Chapala, Mexico.

Lake Chapala is the largest natural freshwater reservoir in Mexico and the third largest lake in Latin America. Lakes are often considered the final deposit of polluting materials; they can be concentrated in the organisms that inhabit them, the water, and the sediments. The PCBs and PBDEs are environmental pollutants highly studied for their known carcinogenic and mutagenic effects. PCB and PBDE bioaccumulation levels were determined in Chirostoma spp., Cyprinus carpio, and Oreochromis aureus. In addition, we monitored the concentrations of PCBs and PBDEs in sediment and water from Lake Chapala were monitored. Samples were collected during two periods, in October 2018 and May 2019. The samples were analyzed by gas chromatography coupled with mass spectrometry. Two bioaccumulation factors were determined in fish, one in relation to the concentration of PCBs and PBDEs in sediments and the other in relation to the concentration of PCBs and PBDEs in water. The PCB levels were 0.55-3.29 ng/g dry weight (dw) in sediments, 1.43-2.98 ng/mL in water, 0.30-5.31 ng/g dw in Chirostoma spp., 1.06-6.07 ng/g dw in Cyprinus carpio, and 0.55-7.20 ng/g dw in Oreochromis aureus. The levels of PBDEs were 0.17-0.35 ng/g dw in sediments, 0.13-0.32 ng/mL in water, 0.01-0.23 ng/g dw in Chirostoma spp., 0-0.31 ng/g dw in Cyprinus carpio, and 0.1-0.22 ng/g dw in Oreochromis aureus. This study provides information for a better understanding of the movement, global distribution, and bioaccumulation of PCBs and PBDEs. The results show that the fish, water, and sediments of Lake Chapala are potential risks to the biota and the local human population.

Increase of 5-HT levels is induced both in mouse brain and HEK-293 cells following their exposure to a non-viral tryptophan hydroxylase construct.

Tryptophan hydroxylase type 2 (Tph2) is the rate-limiting enzyme for serotonin (5-HT) biosynthesis in the brain. Dysfunctional Tph2 alters 5-HT biosynthesis, leading to a deficiency of 5-HT, which could have repercussions on human behavior. In the last decade, several studies have associated polymorphisms of the TPH2 gene with suicidal behavior. Additionally, a 5-HT deficiency has been implicated in various psychiatric pathologies, including alcoholism, impulsive behavior, anxiety, and depression. Therefore, the TPH2 gene could be an ideal target for analyzing the effects of a 5-HT deficiency on brain function. The aim of this study was to use the construct pIRES-hrGFP-1a-Tph2-FLAG to treat CD1-male mice and to transfect HEK-293-cells and then to evaluate whether this treatment increases 5-HT production. 5-HT levels were enhanced 48 h post-transfection, in HEK-293 cells. Three days after the ocular administration of pIRES-hrGFP-1a-Tph2-FLAG to mice, putative 5-HT production was significantly higher than in the control in both hypothalamus and amygdala, but not in the brainstem. Further research will be needed on the possible application of this treatment for psychiatric diseases involving a Tph2 dysfunction or serotonin deficiency.

Prevalence of strongyloidiasis in Peru: systematic review and meta-analysis.

BACKGROUND: Strongyloidiasis is a disease of great public health significance, caused by the parasitic nematodes Strongyloides stercoralis, Strongyloides fuelleborni, and Strongyloides fuelleborni subsp. kellyi. This systematic review and meta-analysis aimed to assess the prevalence of Strongyloides stercoralis infection in Peru. METHODS: The review was based on a literature search in PubMed, SciELO and Google Scholar using the key words or root words "strongyl*" AND "Peru" on 15 July 2020. Eligible studies were published from 1 January 1981 to 15 July 2020 and written in English, Spanish, Italian, or French. RESULTS: We included 21 papers in the analysis. Studies were heterogeneous in terms of study population and diagnostic methods (e.g. Baermann technique, agar, Dancescu or charcoal cultures, serology, string capsule). Prevalence of S. stercoralis ranged from 0.3 to 45%. The pooled proportion of Strongyloides in the general population was 7.34% (95% CI 4.97 to 10.13%). Half the studies were designed to detect parasites in general. In studies designed to detect S. stercoralis, the most widely used diagnostic method was the Baermann technique. CONCLUSION: Prevalence of S. stercoralis in Peru was high but varied by geographic area, techniques for stool examination, and participant characteristics.

Contents and quality of travel tips on malaria in English and Spanish travel blogs.

BACKGROUND: Europe has about 10,000 imported cases of malaria each year, or around 80 cases per 100,000 trips to endemic areas. Non-use of chemoprophylaxis in travellers remains the main reason for this. The proliferation of online travel blogs as a source of advice (sometimes the only one used) for preparing a trip to an endemic area may play a role in the decision to use chemoprophylaxis. The aim of this study was to analyse the information offered on malaria in the main travel blogs in English and Spanish. METHODS: Five hundred travel blogs in English and 100 in Spanish, considered highly relevant were analysed. The relevance were according to different metrics: (1) Alexa Rank; (2) social networks (RRSS) measuring the total followers of Facebook, Twitter, Instagram and YouTube; (3) number of monthly visits using the SEMrush tool; (4) domain authority; and (5) number of backlinks or incoming links using the SEMrush tool. RESULTS: Of the included travel blogs, 57% of those in English and 64% of those in Spanish offered information on malaria, and 79 and 75%, respectively, featured a discussion on malaria written as a blog post or in forum comments. Information on chemoprophylaxis was available in 56.1% of English-language blogs and 10.7% of Spanish-speaking blogs, while its side effects were discussed in 38.6 and 68.8%, respectively (p < 0.001). Content analysis revealed that the information was usually insufficient, incomplete or, more seriously, inaccurate. In many cases, this could discourage users from taking appropriate preventive measures. CONCLUSIONS: Travel blogs in English and Spanish provide low-quality information on malaria. The so-called "travel influencers" must communicate reliable, verified and quality information on malaria on their channels in a way that could contribute to reducing the burden of the disease in travellers.

The adverse effects of the phenylpyrazole, fipronil, on juvenile white shrimp Litopenaeus setiferus.

Chemical pesticides are commonly used world-wide, and they can flow into estuaries and affect non-targeted organisms. We evaluated the effects of six concentrations of the phenylpyrazole, fipronil (0.0, 0.005, 0.01, 0.1, 1.0, and 3.0 µg/L), which are environmentally relevant, on white shrimp Litopenaeus setiferus (initially averaging 0.80 ± 0.08 g/shrimp). Compared with the control, survivorship of shrimp over 45 days declined significantly at the higher concentration treatments. Growth was affected at all concentrations, and the percent weight gain decreased significantly. Inter-molt intervals were longer in all treatments. Changes in swimming and feeding behavior of shrimp were observed under all treatments, and change in body color was observed at higher concentration treatments. Lipid content in shrimp decreased significantly while ash content increased with fipronil concentration. Fipronil adversely affected white shrimp under the concentrations observed in the environment and monitoring of fipronil use is needed in coastal areas.

The Balance of MU-Opioid, Dopamine D2 and Adenosine A2A Heteroreceptor Complexes in the Ventral Striatal-Pallidal GABA Antireward Neurons May Have a Significant Role in Morphine and Cocaine Use Disorders.

The widespread distribution of heteroreceptor complexes with allosteric receptor-receptor interactions in the CNS represents a novel integrative molecular mechanism in the plasma membrane of neurons and glial cells. It was proposed that they form the molecular basis for learning and short-and long-term memories. This is also true for drug memories formed during the development of substance use disorders like morphine and cocaine use disorders. In cocaine use disorder it was found that irreversible A2AR-D2R complexes with an allosteric brake on D2R recognition and signaling are formed in increased densities in the ventral enkephalin positive striatal-pallidal GABA antireward neurons. In this perspective article we discuss and propose how an increase in opioid heteroreceptor complexes, containing MOR-DOR, MOR-MOR and MOR-D2R, and their balance with each other and A2AR-D2R complexes in the striatal-pallidal enkephalin positive GABA antireward neurons, may represent markers for development of morphine use disorders. We suggest that increased formation of MOR-DOR complexes takes place in the striatal-pallidal enkephalin positive GABA antireward neurons after chronic morphine treatment in part through recruitment of MOR from the MOR-D2R complexes due to the possibility that MOR upon morphine treatment can develop a higher affinity for DOR. As a result, increased numbers of D2R monomers/homomers in these neurons become free to interact with the A2A receptors found in high densities within such neurons. Increased numbers of A2AR-D2R heteroreceptor complexes are formed and contribute to enhanced firing of these antireward neurons due to loss of inhibitory D2R protomer signaling which finally leads to the development of morphine use disorder. Development of cocaine use disorder may instead be reduced through enkephalin induced activation of the MOR-DOR complex inhibiting the activity of the enkephalin positive GABA antireward neurons. Altogether, we propose that these altered complexes could be pharmacological targets to modulate the reward and the development of substance use disorders.