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The opioid epidemic was triggered by an overprescription of opioid analgesics. In the treatment of chronic pain, repeated opioid administrations are required which ultimately lead to tolerance, physical dependence, and addiction. A possible way to overcome this conundrum consists of a co-medication that maintains the analgesic benefits of opioids while preventing their adverse liabilities. YHS, the extract of the plant Corydalis yanhusuo, has been used as analgesic in traditional Chinese medicine for centuries. More recently, it has been shown to promote analgesia in animal models of acute, inflammatory, and neuropathic pain. It acts, at least in part, by inhibiting the dopamine D2 receptor, suggesting that it may be advantageous to manage addiction. We first show that, in animals, YHS can increase the efficacy of morphine antinociceptive and, as such, decrease the need of the opioid. We then show that YHS, when coadministered with morphine, inhibits morphine tolerance, dependence, and addiction. Finally, we show that, in animals treated for several days with morphine, YHS can reverse morphine dependence and addiction. Together, these data indicate that YHS may be useful as a co-medication in morphine therapies to limit adverse morphine effects. Because YHS is readily available and safe, it may have an immediate positive impact to curb the opioid epidemic.

SLL-039 (N-cyclopropylmethyl-7α−4′-(N’-benzoyl) amino-phenyl-6,14-endoethano-tetrahydronorthebaine) and SLL-1206 (N-cyclopropylmethyl-7α−3′-(p-methoxybenzyl) amino-phenyl-6,14-endoethano-tetrahydronorthebaine) are two 4,5-epoxymorphinan-based high selective κ receptor agonists that we recently discovered. In the present study we characterized their pharmacological properties in comparison with arylacetamide-based typical κ agonist U50,488H. We showed that both SLL-039 and SLL-1206 produced potent and long-lasting antinociceptive actions in three different rodent models of pain via activation of κ opioid receptor. In hot-plate assay, the antinociceptive potency of SLL-039 and SLL-1206 increased about 11-and 17.3-fold compared to U50,488H and morphine, respectively, with ED(50) values of 0.4 mg/kg. Following repeated administration, SLL-1206, SLL-039, and U50,488H all developed analgesic tolerance tested in hot-plate assay. U50,488H and SLL-039 produced antipruritic effects in a dose-dependent manner, whereas SLL-1206 displayed some antipruritic effects only at very low doses. In addition, SLL-1206 was capable of decreasing morphine-induced physical dependence. More importantly, SLL-039 and SLL-1206 at effective analgesic doses did not cause sedation and conditioned place aversion (CPA), whereas U50,488H did. In comparison with SLL-039, SLL-1206 caused similar antinociceptive responses, but fewer sedation and CPA. In conclusion, our results suggest that SLL-039 and SLL-1206 have potential to be developed as novel analgesic agents, and 4,5-expoxymorphinan scaffold is an attractive structure for the development of selective κ agonists with fewer side effects.

Alcohol use is associated with a significant variety of harms to both the individual and society. Screening for alcohol use disorders should be part of most clinical assessments. It is particularly important to identify people with features of physical dependence as they can be at risk of complications on alcohol withdrawal. Identification and brief advice can be effective at targeting drinking in low-risk individuals, but higher risk individuals with more severe alcohol use disorders may require specialist interventions. Alcohol withdrawal should be treated with long-acting benzodiazepines, ideally in a planned way as part of a comprehensive treatment plan including psychosocial intervention. There is a risk of neurotoxicity associated with repeated alcohol withdrawal and detoxification, so the relative risks and benefits to patient should always be weighed up. Wernicke–Korsakoff's syndrome should be considered in all individuals with a significant alcohol use disorder and the presence of a single suggestive symptom should be sufficient to prompt treatment. Alcohol use disorders are relapsing and remitting conditions; therefore it is important that health professionals convey a sense of hope and optimism to promote a patient's sense of self-efficacy as they work towards recovery.

Background: Atorvastatin exerts neuroprotective effects on the treatment of central nervous system disorders. Morphine analgesic tolerance and dependence remain as major concerns in medicine. Nitric oxide (NO) pathway mediates the development of opioid analgesic tolerance and dependence, as well as atorvastatin neuroprotection. Objectives: The present study aimed to assess the possible involvement of the NO/cGMP pathway in the process of the effects of atorvastatin on morphine physical dependence. Methods: Dependence was induced by repetitive injection of morphine sulfate. Naloxone was injected at the dose of 4 mg/kg on the last day of the experiment to assess withdrawal signs. Animals received atorvastatin (1, 5, 10, and 20 mg/kg, orally). Nitric oxide synthase (NOS) inhibitors and ODQ were injected before protective dose of atorvastatin. The gene expression of NOS isoforms was evaluated by real-time PCR. Thereafter, the hippocampal levels of cGMP and nitrite were measured. Results: Treatment with atorvastatin 10 mg/kg significantly attenuated naloxone-induced withdrawal behaviours. The administration of L-NAME, aminoguanidine, and ODQ before atorvastatin enhanced its effects. The treatment with atorvastatin significantly decreased the nitrite and cGMP levels as well as NOS gene expression in the hippocampus of dependent animals. Conclusions: It can be concluded that atorvastatin, possibly, through inducible NOS, could alleviate morphine dependence and withdrawal signs.

Aims Dezocine and pentazocine, widely prescribed in China for postoperative pain, were initially considered as mixed agonist/antagonist targeting μ-opioid receptors (MORs) and κ-opioid receptors (KORs). However, dezocine has been revealed to alleviate chronic neuropathic pain through MOR activation and norepinephrine reuptake inhibition (NRI). This study investigated dezocine- and pentazocine-induced antinociception and physical dependence development, compared to the typical MOR-NRI opioid tapentadol. Main methods Calcium mobilization assay was conducted to assess the potency of the drugs while hot-plate test was performed to compare the antinociception. Physical dependence development was compared with morphine. Key findings Treatment with dezocine, pentazocine and tapentadol stimulated calcium mobilization in HEK293 cells stably expressed MORs but not KORs, whereas dezocine and pentazocine inhibited KOR activities. Subcutaneously injected dezocine-, tapentadol- and pentazocine-induced antinociception dose-dependently, in hot-plate test. Intrathecally injected MOR antagonist CTAP, norepinephrine depletor 6-OHDA and α2-adrenoceptor (α2-AR) antagonist yohimbine partially antagonized dezocine, pentazocine and tapentadol antinociception. Whereas specific KOR antagonist GNTI did not alter their antinociception, the putative inverse KOR agonist nor-BNI reduced dezocine and pentazocine antinociception. Moreover, combined CTAP and 6-OHDA or yohimbine blocked dezocine and tapentadol antinociception but displayed the same partial inhibition on pentazocine antinociception as CTAP alone. Furthermore, compared to morphine and pentazocine, long-term treatment with dezocine and tapentadol produced much less physical dependence-related withdrawal signs, which were restored by spinal 6-OHDA or yohimbine treatment. Significance Our findings illustrated that dezocine and tapentadol, but not pentazocine, exert remarkable antinociception in nociceptive pain with less abuse liability via dual mechanisms of MOR activation and NRI.

Opioids account for 69,000 overdose deaths per annum worldwide and cause serious side effects. Safer analgesics are urgently needed. The endogenous opioid peptide Leu-Enkephalin (Leu-ENK) is ineffective when introduced peripherally due to poor stability and limited membrane permeability. We developed a focused library of Leu-ENK analogs containing small hydrophobic modifications. N-pivaloyl analog KK-103 showed the highest binding affinity to the delta opioid receptor (68% relative to Leu-ENK) and an extended plasma half-life of 37 h. In the murine hot-plate model, subcutaneous KK-103 showed 10-fold improved anticonception (142%MPE·h) compared to Leu-ENK (14%MPE·h). In the formalin model, KK-103 reduced the licking and biting time to ~50% relative to the vehicle group. KK-103 was shown to act through the opioid receptors in the central nervous system. In contrast to morphine, KK-103 was longer-lasting and did not induce breathing depression, physical dependence, and tolerance, showing potential as a safe and effective analgesic.

Best practice guidelines for the safe and compassionate care of critically ill children necessitates the use of sedation to ensure adequate ventilation, patient safety and comfort. Prolonged use of sedation can result in tolerance, physical dependence and iatrogenic withdrawal syndrome if medications are weaned too quickly.In the context of medication errors related to parent administration of outpatient sedation weans, we set out to improve the safety of children weaning from sedatives.A retrospective analysis was completed. Quality improvement was guided by using Plan-Do-Study-Act cycles.An evidence-based post PICU sedation weaning guideline was created and implemented over time with ongoing education, and review of progress with staff members with pre-post evaluation.Post intervention, there were significant differences in the numbers of patients discharged on home weaning from both opioids and benzodiazepines (11%, n = 24/219 pre; 3%, n = 7/233 post; p 0.005). The number of patients discharged with a methadone wean decreased (7%, n = 16/219 pre; 0%, 0/233 post; p = 0.03). Despite these differences, there were no significant differences in the median hospital length of stay (42 pre; 39 post; p = 0.35). Post implementation more children had mild to moderate symptoms of withdrawal (11% pre; 21% post; p 0.005) as compared to pre-implementation, however, the percentage of severe symptoms remained consistently low (0.6% pre; 1% post; p = 0.11).Implementation of an evidence-based post PICU weaning guideline significantly reduced the number of patients discharged on potentially dangerous medications with modest increases in mild-moderate symptoms of withdrawal and no significant change in length of stay or the incidence of severe symptoms of withdrawal.

The prevalence of insomnia, depression and anxiety have recently been increasing (Kessler et al., 2005) with approximately 18.4% of the Brazilian population having experienced depression at least once during their lifetimes. These data characterize Brazil as the developing country with the largest number of people suffering from this disease (WHO, 2018). Depression is commonly accompanied by anxiety disorders and chronic psychiatric conditions with an estimated prevalence of approximately 29% (Kessler et al., 2005), which results in functional impairment that is associated with significant social costs. Treatment of these conditions includes psychological therapy and antidepressants. These drugs, such as benzodiazepines (BZDs), have been widely studied since the 1960s (Llorente et al., 2000) (WHO, 2018). BZDs are used by 9–25% of the elderly population aged 65 years of age and over, mainly among women (15–21.7% in Brazil, 9.9% in the United States, 24% in Canada and 25% in Sweden) (Jorm et al., 2000, Alvarenga et al., 2008, Johnell and Fastbom, 2009, Leggett et al., 2015). BZDs can be divided into two categories, anxiolytics and hypnotics, and can be used as anticonvulsants due to their muscle relaxant effects (De Almeida et al., 2008). As with all central-acting drugs, BZDs have side effects, such as decreased psychomotor activity, memory loss, physical dependence on long-term treatments, (Longo et al., 2000, Uzun et al., 2010) and hyposalivation and/or xerostomia, which is one of the main adverse effects described in the literature (Guggenheimer and Moore, 2003, Lambrecht et al., 2013, Raghavan et al., 2014). BZDs are among the drugs with the highest rates of complaints by patients in dental offices (Smith and Burtner, 1994) where these drugs are prescribed to reduce anxiety related to dental treatments of non-cooperative patients (Zaclikevis et al., 2009). Among the licensed BZDs, Lorazepam is one of the most widely used drugs for both insomnia and anxiety (Amato et al., 2010), particularly among elderly individuals with anxiety disorders and related conditions (Pomara et al., 2015). Previous studies, by our research group, demonstrated the damage Lorazepam and midazolam, another BDZ commonly prescribed for anxiety, caused to the acinar cells of parotid glands (Rinaldi et al., 2015, Mattioli et al., 2016, Rinaldi et al., 2018). We observed that the chronic use of BZDs significantly decreased the number and proliferation of acinar cells, reduced salivary flow and increased cell volume. In light of this, we hypothesize that the reduction in the number of acinar cells caused by Lorazepam in the salivary glands is possibly due to an apoptotic effect on these cells of the parotid glands of rats caused by the chronic use of this drug. Apoptosis plays a fundamental role in the elimination of unwanted, damaged or infected cells in multicellular organisms and serves as an important biological process in cellular development, differentiation and proliferation (So et al., 2016). The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labeling (TUNEL) (Tilly, 1996) technique is the gold standard test employed to detect apoptotic cells (Burattini et al., 2009, Heisler-Taylor et al., 2018). Because of the its wide-spread use of TUNEL, there is no need to use another technique to detect apoptotic cells. The literature lacks studies demonstrating Lorazepam-induced apoptosis in acinar cells. The aim of this study was to evaluate the apoptotic action of a BZD on the acinar cells of the parotid glands of rats by quantification of the number of apoptotic cell nuclei (NCA), the number of acinar cells (N) and the immunoexpression of nuclear proliferation cell proliferation (PCNA) protein.

Introduction The major aim of this study was to test whether abstinence from e-cigarettes causes withdrawal symptoms in former smokers. Methods We conducted an unblinded, within-participants, pre–post clinical trial in which 109 former smokers who were current daily electronic cigarette (e-cigarette) users used their own e-cigarette for 7 days followed by 6 days of biologically confirmed abstinence engendered via an escalating contingency payment system. Participants monitored symptoms of nicotine withdrawal daily via an Interactive Voice Response system. They also attended three laboratory visits per week for carbon monoxide and cotinine testing to verify abstinence. Results Half of participants completely abstained for a week. All the Diagnostic and Statistical Manual, Fifth Edition (DSM-5) tobacco withdrawal symptoms, craving for e-cigarettes, craving for tobacco cigarettes, and the four possible new withdrawal symptoms (anhedonia, impulsivity, mood swings, and positive affect) increased during abstinence. Weight increased and heart rate decreased with abstinence. Symptoms showed the prototypical inverted U time pattern of a withdrawal state. The magnitude of withdrawal appeared to be somewhat less than that in a prior study of abstinent daily tobacco cigarette smokers. More severe withdrawal on the first 2 days of abstinence did not predict abstinence on the last day of the study. Conclusions Former smokers who are daily e-cigarette users transfer physical dependence on tobacco cigarettes to dependence on e-cigarettes. The severity of withdrawal from e-cigarettes appears to be only somewhat less than that from daily tobacco cigarette use. Replication tests that include placebo controls, testing for pharmacological specificity, and including never-smokers, non-daily e-cigarette users and dual users are indicated. Implications Our results indicate e-cigarettes can maintain physical dependence. This adverse effect should be included in any risk vs. benefit calculation. Also, potential and current e-cigarette users should be informed that abrupt cessation of e-cigarettes can cause withdrawal symptoms. Trial registration NCT02825459.

Most of the sedative drugs cause dose-dependent depression of the central nervous system (CNS) leading to hypnosis and possibly anaesthesia, however, these agents are associated with some side effects ranging from digestive, respiratory, immune system dysfunctions, cognitive function deterioration, tolerance, and physical dependence, hence investigations of newer and safer agents is therefore imperative. The current study sought to investigate the sedative-hypnotic effects of methanolic stem bark extract of Ficus abutilifolia in mice. Phytochemical constituents and sedative-hypnotic activity of the extract were investigated. Twenty Swiss albino mice were used for the experiment, the animals were randomly divided into four groups of five mice each. The mice in groups 1 and 2 were injected with the extract at the dose of 100 and 200 mg/kg, respectively, those in group 3 were injected with xylazine at the dose rate of 10 mg/kg, while the control group 4 mice received nothing at the beginning of the experiment. All the four experimental groups were injected with ketamine at the dose rate of 100 mg/kg after 30 min, all the treatments during the experimental trial were administered intraperitoneally (IP). Phytochemical analysis of the stem bark extract revealed the presence of carbohydrates, reducing sugars, cardiac glycosides, cardinolides, steroids and triterpenes, saponins, tannins, condensed tannins and flavonoids, while, anthraquinones, anthracene derivates and alkaloids were absent. The results show no significant difference (P ≥ 0.05) on the sleep onset time between the four groups, however, statistically significant difference (P

Background The marked increase in mis-use of prescription opioids has greatly affected our society. One potential solution is to develop improved analgesics which have agonist action at both mu opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptors. BU10038 is a recently identified bifunctional MOP/NOP partial agonist. The aim of this study was to determine the functional profile of systemic or spinal delivery of BU10038 in primates after acute and chronic administration. Methods A series of behavioural and physiological assays have been established specifically to reflect the therapeutic (analgesia) and side-effects (abuse potential, respiratory depression, itch, physical dependence, and tolerance) of opioid analgesics in rhesus monkeys. Results After systemic administration, BU10038 (0.001–0.01 mg kg−1) dose-dependently produced long-lasting antinociceptive and antihypersensitive effects. Unlike the MOP agonist oxycodone, BU10038 lacked reinforcing effects (i.e. little or no abuse liability), and BU10038 did not compromise the physiological functions of primates including respiration, cardiovascular activities, and body temperature at antinociceptive doses and a 10–30-fold higher dose (0.01–0.1 mg kg−1). After intrathecal administration, BU10038 (3 μg) exerted morphine-comparable antinociception and antihypersensitivity without itch scratching responses. Unlike morphine, BU10038 did not cause the development of physical dependence and tolerance after repeated and chronic administration. Conclusions These in vivo findings demonstrate the translational potential of bifunctional MOP/NOP receptor agonists such as BU10038 as a safe, non-addictive analgesic with fewer side-effects in primates. This study strongly supports that bifunctional MOP/NOP agonists may provide improved analgesics and an alternative solution for the ongoing prescription opioid crisis.

Background and Aim: Sedative drugs mostly cause dose-dependent depression of the central nervous system which results in hypnosis and anesthesia possibly; however, these agents are associated with some side effects ranging respiratory, digestive, immune system dysfunctions, tolerance, cognitive function deterioration, and physical dependence; hence, investigations of newer and safer agents are, therefore, imperative. The current study was aimed at investigating the sedative-hypnotic (S-H) effects of the methanol leaf extract of Ficus exasperata in mice. Materials and Methods: Phytochemical screening of the leaf extract was conducted, and S-H activity of the plant extract was evaluated. Twenty Swiss Albino mice were randomly divided into four groups of five mice each. The mice in Groups A and B were injected with the extract intraperitoneally (IP) at the dose rate of 100 and 200 mg/kg, respectively, those in Group C were injected with xylazine at the dose rate of 10 mg/kg, while Group D mice received distilled water at the dose rate of 2 ml/kg. All the four experimental groups were injected with ketamine (IP) at the dose rate of 100 mg/kg after 30 min. Results: Phytochemical analysis of the extract revealed the presence of carbohydrates, cardiac glycosides, reducing sugars, steroids and triterpenes, saponins, tannins, condensed tannins, and flavonoids, while anthraquinones, anthracene derivatives, and alkaloids were absent. Results from the S-H evaluation show no significant difference (p≥0.05) on the onset of sleep time between the four experimental groups; however, statistically significant difference (p≤0.05) was recorded in the sleep duration time between the groups treated with only ketamine and the other experimental groups pre-treated with either the extract or xylazine before ketamine administration. The group pre-treated with a high dose of the plant extract (200 mg/kg) and the treated with ketamine after 30 min exhibited longer sleeping duration time. The plant extract, xylazine and ketamine, sedated the mice for some period of time after arousal from sleep. Conclusion: Our finding suggests that methanol leaf extract of F. exasperata possesses S-H potential that may require further scientific investigations.

Morphine is a potent opioid analgesic used to alleviate moderate or severe pain, but the development of drug tolerance and dependence limits its use in pain management. Our previous studies showed that the candidate protein for I1 imidazoline receptor, imidazoline receptor antisera-selected (IRAS)/Nischarin, interacts with μ opioid receptor (MOR) and modulates its trafficking. However, there is no report of the effect of IRAS on morphine tolerance and physical dependence. In the present study, we found that IRAS knockout (KO) mice showed exacerbated analgesic tolerance and physical dependence compared to wild-type (WT) mice by chronic morphine treatment. Chronic morphine treatment down-regulated the expression of MOR in spinal cord of IRAS KO mice, while had no significant effect on MOR expression in WT mice. We observed the compensatory increase of cAMP accumulation in spinal cord after morphine tolerance, and this change was more significant in KO mice than WT mice. Furthermore, KO mice showed more elevation in the phosphorylation of AMPA receptor GluR1-S845 than WT mice, while the total expression of GluR1 remained unchanged after morphine dependence. Altogether, these data suggest that IRAS may play an important role in the development of morphine tolerance and physical dependence in vivo through modulating MOR expression, as well as AMPA GluR1-S845 phosphorylation, which might be one of the mechanisms underlying the development of opiate addiction.

Here, we aimed to investigate the effects of fluoxetine on morphine-induced analgesia, as well as preventive effects of it on morphine induced tolerance and dependence in mice. We also elucidate the involvement of L-type Ca2+ channels in these phenomena. To induce morphine tolerance, mice were treated with morphine (50 mg/kg) for 3 consecutive days. To evaluate the involvement of the calcium channel in the effects of fluoxetine (5, 20 mg/kg), combination ineffective doses of the two L-type calcium channel blockers, nimodipine (5 mg/kg) or diltiazem (20 mg/kg) with flouxetine were used with each morphine dose. Nociceptive behavior was evaluated using hot-plate test, while physical dependence assessed by naloxone-precipitated withdrawal on the fourth day of experiment. The expression of Cav1.2 and Cav1.3 subunits of the L-type calcium channels in cortex and mesolimbic tissues were measured using western immunoassay. Results showed that co-administration of fluoxetine (20 mg/kg) with morphine increased its acute analgesia effect and prevented the induction of morphine antinociceptive tolerance and physical dependence in mice. Moreover, these effects was potentiated by pre-treatment with diltiazem or nimodipine. Results also showed up-regulation of the Cav1.3 and Cav1.2 expression in the cerebral cortex and mesolimbic regions through the development of morphine dependence. Moreover, chronic administration of fluoxetine with morphine reduced the observed up-regulation of Cav1.3 and Cav1.2 expression in cortex and mesolimbic tissues. Our data indicated that co-administering of fluoxetine with morphine could potentiate the antinociceptive effect of morphine, prevent morphine analgesia tolerance and attenuated the morphine withdrawal signs during induction phases. Moreover, we also pointed out for the first time the role of L-type Ca2+ channel channels in the modulatory effects of fluoxetine on the morphine-related effects.

Nicotine has well known long term neurovegetative effects but their relationship to tobacco dependence is unknown. We study the change in the neurovegetative tone induced after sprayed nicotine, equivalent to one cigarette in smokers and non-smokers, and its relationship of this change with smoking addiction.

Objectives: Recently, opioid abuse and related overdoses have increased warranting the need for research directed against the opioid epidemic. Previous studies identified that patients on opioid therapy may become zinc deficient and that zinc, in a murine model, may antagonistically affect the opioid receptor. 13 Further understanding the relationship between opioid use and zinc deficiency may mitigate the opioid epidemic. Methods: A retrospective study was conducted to identify zinc (Zn2+) deficiencies among post-operative total hip arthroplasty (THA) patients. On post-operative day one, patients had routine blood tests, including Zn2+ plasma levels. Patients were considered Zn2+-deficient if their Zn2+ plasma was < 56 μg/dL (Reference: 56-134 μg/dL). Upon discharge from the hospital, the patients’ inpatient opioid medication consumption per day was determined by dividing total morphine milligram equivalents (MMEs) by length of stay. A Student's t-test was performed to compare the total MMEs for Zn2+-deficient patients versus Zn2+-normal patients. A univariate analysis followed by multiple linear regression was performed to identify demographic or surgical predictors of MMEs/day. Results: For Zn2+-deficient patients, the total MMEs/day was 33.62 ( ± 27.06), as compared to Zn2+-normal patients who consumed 16.22 ( ±16.01) MMEs/day (p = 0.031). The univariate analysis and multiple linear regression showed that patients’ Zn2+ status had a significant contribution toward predicting MMEs/day, with p = 0.022 and p = 0.04, respectively. Conclusion: The results of this study suggest that Zn2+ deficiency may potentiate opioid consumption. Thus, Zn2+ supplementation may be a simple approach to reducing opioid addiction and dependence.

The boxed warning for drugs in the benzodiazepine class has been strengthened to further emphasize the risk of overdose and death, especially if combined with opioids, alcohol, or illicit drugs, and the risk of abuse, misuse, addiction, physical dependence, and withdrawal.

Bulleyaconitine A (BAA), a C19-diterpenoid alkaloid, has been prescribed as a nonnarcotic analgesic to treat chronic pain over four decades in China. The present study investigated its inhibition in morphine-induced withdrawal symptoms, conditioned place preference (CPP) and locomotor sensitization, and then explored the underlying mechanisms of actions. Multiple daily injections of morphine but not BAA up to 300 μg/kg/day into mice evoked naloxone-induced withdrawal symptoms (i.e., shakes, jumps, genital licks, fecal excretion and body weight loss), CPP expression, and locomotor sensitization. Single subcutaneous BAA injection (30–300 μg/kg) dose-dependently and completely attenuated morphine-induced withdrawal symptoms, with ED50 values of 74.4 and 105.8 μg/kg in shakes and body weight loss, respectively. Subcutaneous BAA (300 μg/kg) also totally alleviated morphine-induced CPP acquisition and expression and locomotor sensitization. Furthermore, subcutaneous BAA injection also specifically stimulated dynorphin A expression in microglia but not astrocytes or neurons in nucleus accumbens (NAc) and hippocampal, measured for gene and protein expression and double immunofluorescence staining. In addition, subcutaneous BAA-inhibited morphine-induced withdrawal symptoms and CPP expression were totally blocked by the microglial metabolic inhibitor minocycline, dynorphin A antiserum, or specific KOR antagonist GNTI, given intracerebroventricularly. These results, for the first time, illustrate that BAA attenuates morphine-induced withdrawal symptoms, CPP expression, and locomotor sensitization by stimulation of microglial dynorphin A expression in the brain, suggesting that BAA may be a potential candidate for treatment of opioids-induced physical dependence and addiction.

Background: Caffeine is from methyl xanthine class which mainly stimulates the central nervous system. Caffeine is one of the most widely used psychoactive drugs in the world. It is commonly found in beverages, chocolates, cocoa containing products and in medications. Caffeine is recognized as legal and its consumption is unregulated all over of the world. Objectives: The objective of this study is to summarize the impact of caffeine on behavioral and health alterations, in both controlled and overdose conditions. Moreover, the specifics of caffeine withdrawal and a number of guidelines on how to handle reducing or quitting caffeine intake altogether is also highlighted. Methodology: To compose this review, more than seventy research and review articles were overviewed that were published over a period of last twenty years, using Google Scholar search engines. Results: Caffeine regular use causes physical dependence which may become the caffeine withdrawal sign that can consequently harm normal working. The most important function of caffeine is that it can reversibly blocks the adenosine performance on its receptor and as a result which prevent the beginning of drowsiness encouraged by adenosine. Caffeine also stimulates certain portions of the autonomic nervous system symptom including fatigue, drowsiness, depressed mood, headache, difficulty concentrating, decreased energy, decreased contentedness, decreased alertness, irritability and unclear headed. Conclusion: It is concluded that utilization of caffeine in a prescribed dose can have good impact on health and may decrease addictive symptoms. Additionally, reducing caffeine dosage over a six week period guides to successful, long-term caffeine cessation with very few side effects.

Preclinical opioid research using animal models not only provides mechanistic insights into the modulation of opioid analgesia and its associated side effects, but also validates drug candidates for improved treatment options for opioid use disorder. Non-human primates (NHPs) have served as a surrogate species for humans in opioid research for more than five decades. The translational value of NHP models is supported by the documented species differences between rodents and primates regarding their behavioral and physiological responses to opioid-related ligands and that NHP studies have provided more concordant results with human studies. This review highlights the utilization of NHP models in five aspects of opioid research, i.e., analgesia, abuse liability, respiratory depression, physical dependence, and pruritus. Recent NHP studies have found that (1) mixed mu opioid and nociceptin/orphanin FQ peptide receptor partial agonists appear to be safe, non-addictive analgesics and (2) mu opioid receptor- and mixed opioid receptor subtype-based medications remain the only two classes of drugs that are effective in alleviating opioid-induced adverse effects. Given the recent advances in pharmaceutical sciences and discoveries of novel targets, NHP studies are posed to identify the translational gap and validate therapeutic targets for the treatment of opioid use disorder. Pharmacological studies using NHPs along with multiple outcome measures (e.g., behavior, physiologic function, and neuroimaging) will continue to facilitate the research and development of improved medications to curb the opioid epidemic.

Abuse and misuse of prescription drugs remains an ongoing concern in the USA and worldwide; thus, all centrally active new drugs must be assessed for abuse and dependence potential. Sphingosine-1-phosphate (S1P) receptor modulators are used primarily in the treatment of multiple sclerosis. Among the new S1P receptor modulators, siponimod, ozanimod, and ponesimod have recently been approved in the USA, European Union (EU), and other countries. This review of literature and other public data has been undertaken to assess the potential for abuse of S1P receptor modulators, including ozanimod, siponimod, ponesimod, and fingolimod, as well as several similar compounds in development. The S1P receptor modulators have not shown chemical or pharmacological similarity to known drugs of abuse; have not shown abuse or dependence potential in animal models for subjective effects, reinforcement, or physical dependence; and do not have adverse event profiles demonstrating effects of interest to individuals who abuse drugs (such as sedative, stimulant, mood-elevating, or hallucinogenic effects). In addition, no reports of actual abuse, misuse, or dependence were identified in the scientific literature for fingolimod, which has been on the market since 2010 (USA) and 2011 (EU). Overall, the data suggest that S1P receptor modulators are not associated with significant potential for abuse or dependence, consistent with their unscheduled status in the USA and internationally.

One of the main challenges in contemporary medicinal chemistry is the development of safer analgesics, used in the treatment of pain. Currently, moderate to severe pain is still treated with the “gold standard” opioids whose long-term often leads to severe side effects. With the discovery of biased agonism, the importance of this area of pharmacology has grown exponentially over the past decade. Of these side effects, tolerance, opioid misuse, physical dependence and substance use disorder (SUD) stand out, since these have led to many deaths over the past decades in both USA and Europe. New therapeutic molecules that induce a biased response at the opioid receptors (MOR, DOR, KOR and NOP receptor) are able to circumvent these side effects and, consequently, serve as more advantageous therapies with great promise. The concept of biased signaling extends far beyond the already sizeable field of GPCR pharmacology and covering everything would be vastly outside the scope of this review which consequently covers the biased ligands acting at the opioid family of receptors. The limitation of quantifying bias, however, makes this a controversial subject, where it is dependent on the reference ligand, the equation or the assay used for the quantification. Hence, the major issue in the field of biased ligands remains the translation of the in vitro profiles of biased signaling, with corresponding bias factors to in vivo profiles showing the presence or the lack of specific side effects. This review comprises a comprehensive overview of biased ligands in addition to their bias factors at individual members of the opioid family of receptors, as well as bifunctional ligands.