Abdulrahman Mohammed I Almatroudi

Bio: Abdulrahman Mohammed I Almatroudi is an academic researcher from University of Bath. The author has contributed to research in topics: Buprenorphine & κ-opioid receptor. The author has an hindex of 3, co-authored 8 publications receiving 74 citations.

Combined administration of buprenorphine and naltrexone produces antidepressant-like effects in mice.

Abstract: Opiates have been used historically for the treatment of depression. Renewed interest in the use of opiates as antidepressants has focused on the development of kappa opioid receptor (κ-receptor) antagonists. Buprenorphine acts as a partial µ-opioid receptor agonist and a κ-receptor antagonist. By combining buprenorphine with the opioid antagonist naltrexone, the activation of µ-opioid receptors will be reduced and the κ-antagonist properties enhanced. We have established that a combination dose of buprenorphine (1 mg/kg) with naltrexone (1 mg/kg) functions as a short-acting κ-antagonist in the mouse tail withdrawal test. Furthermore, this dose combination is neither rewarding nor aversive in the conditioned place preference paradigm, and is without significant locomotor effects. We have shown for the first time that systemic co-administration of buprenorphine (1 mg/kg) with naltrexone (1 mg/kg) in CD-1 mice produced an antidepressant-like response in behaviours in both the forced swim test and novelty induced hypophagia task. Behaviours in the elevated plus maze and light dark box were not significantly altered by treatment with buprenorphine alone, or in combination with naltrexone. We propose that the combination of buprenorphine with naltrexone represents a novel, and potentially a readily translatable approach, to the treatment of depression.

Antidepressant-like effects of BU10119, a novel buprenorphine analogue with mixed κ/μ receptor antagonist properties, in mice.

Abstract: Background and Purpose The κ receptor antagonists have potential for treating neuropsychiatric disorders. We have investigated the in vivo pharmacology of a novel buprenorphine analogue, BU10119, for the first time. Experimental Approach To determine the opioid pharmacology of BU10119 (0.3–3 mg·kg−1, i.p.) in vivo, the warm-water tail-withdrawal assay was applied in adult male CD1 mice. A range of behavioural paradigms was used to investigate the locomotor effects, rewarding properties and antidepressant or anxiolytic potential of BU10119. Additional groups of mice were exposed to a single (1 × 2 h) or repeated restraint stress (3× daily 2 h) to determine the ability of BU10119 to block stress-induced analgesia. Key Results BU10119 alone was without any antinociceptive activity. BU10119 (1 mg·kg−1) was able to block U50,488, buprenorphine and morphine-induced antinociception. The κ antagonist effects of BU10119 in the tail-withdrawal assay reversed between 24 and 48 h. BU10119 was without significant locomotor or rewarding effects. BU10119 (1 mg·kg−1) significantly reduced the latency to feed in the novelty-induced hypophagia task and reduced immobility time in the forced swim test, compared to saline-treated animals. There were no significant effects of BU10119 in either the elevated plus maze or the light–dark box. Both acute and repeated restraint stress-induced analgesia were blocked by pretreatment with BU10119 (1 mg·kg−1). Parallel stress-induced increases in plasma corticosterone were not affected. Conclusions and Implications BU10119 is a mixed κ/μ receptor antagonist with relatively short-duration κ antagonist activity. Based on these preclinical data, BU10119 has therapeutic potential for the treatment of depression and other stress-induced conditions.

Tianeptine: An Atypical Antidepressant with Multimodal Pharmacology

Abstract: Background: Tianeptine is an atypical antidepressant marketed as Stablon since the late 1980’s. While chemically very similar to tricyclic antidepressants, tianeptine was thought to have the apparently paradoxical mechanism of action of enhancing serotonin reuptake. However, recent data highlight a multimodal pharmacology for tianeptine including actions at glutamatergic synapses (inhibiting NMDA receptors and an indirect effect on AM-PA receptors) coupled with agonist effects at mu opioid receptors (-receptors). Objective: We have reviewed clinical and preclinical data for tianeptine to provide a compre-hensive study of its pharmacology. Results: Clinical trials show that tianeptine is at least as efficacious as first-line antidepres-sant treatments, with improved tolerability as it is significantly less prone to disrupting the patient's normal functionality. Tianeptine appears more efficacious in males than females, although these gender-specific differences may be accounted for by pharmacokinetics. Pre-clinical data suggest that the ability to stabilise glutamatergic neurotransmission may underlie tianeptine’s ability to improve cognitive function and anxiety-related symptoms. Alternative-ly, μ-receptor activation of the mTOR signalling pathway could lead tianeptine to be a fast-acting antidepressant. Agonist actions at μ-receptors could also explain the potential abuse li-ability and dependence issues seen with high dose tianeptine. Conclusion: Tianeptine itself is off patent, but it still holds much promise as an experimental tool yielding valuable insights into the molecular mechanisms underlying depression.

The antidepressant-like effects of combination buprenorphine/naltrexone in the novelty-induced hypophagia task in mice

Abstract: Antagonists at kappa-opioid receptors have been proposed as novel antidepressants. The standard high-affinity, selective kappa-antagonists have a long lasting duration of action which potentially limits their use (Carroll and Carlezon 2013. J Med Chem 56: 2178-2195). Buprenorphine is a partial mu-opioid receptor agonist and a kappa-antagonist, while naltrexone is a non-selective opioid antagonist. We have previously shown that the combination of buprenorphine (1mg/kg) with naltrexone (1mg/kg) produced a functional short-acting kappa-antagonist that was non-sedating and non-rewarding in mice. Here, we report the effects of this combination treatment on depression-related behaviour. Adult male CD-1 mice (8-9 weeks) were used. For novelty-induced hypophagia, mice were individually housed and trained for 3 days to consume condensed milk. On test days, mice were injected intraperitoneally (10 ml/kg) with saline, buprenorphine alone (1 mg/kg), naltrexone alone (1 mg/kg), buprenorphine/naltrexone combination (1 mg/kg), norBNI (10mg/kg) or fluoxetine (20 mg/kg) one hour prior to testing behaviour. The latency to drink and consumption were recorded in the home cage (day 4) and in the novel cage (day5). One-way ANOVA, revealed that there was a significant effect of drug treatment on the latency to drink in the novel cage (F (5, 54) =8.5, P<0.001) but not consumption (F (5, 54) =1, P=0.4). The combination of buprenorphine/naltrexone produced antidepressant-like effects, significantly reducing the latency to drink in the novel cage, compared with controls. Interestingly, the effects of the combination treatment were similar to naltrexone alone. We have previously shown that mixed mu-/kappa-opioid receptor antagonists have antidepressant and anxiolytic potential (Casal-Dominguez et al. 2013 J Psychopharm 27:192-202). We are investigating whether combination buprenorphine/ naltrexone may also have anxiolytic potential in mice.

Antidepressant-like effects of BU10119, a novel buprenorphine analogue with mixed kappa/mu opioid receptor antagonist properties, in mice

Abstract: Background and Purpose Kappa-opioid receptor antagonists have potential for treating neuropsychiatric disorders. We have investigated the in vivo pharmacology of a novel buprenorphine analogue, BU10119, for the first time. Experimental Approach To determine the opioid pharmacology of BU10119 (0.3-3 mg/kg, i.p.) in vivo, the warm-water tail withdrawal assay was used in adult male CD1 mice. A range of behavioural paradigms was used to investigate the locomotor effects, rewarding properties and antidepressant or anxiolytic potential of BU10119. Additional groups of mice were exposed to a single (1 x 2h) or repeated restraint stress (3 x daily 2h) to determine the ability of BU10119 to block stress-induced analgesia. Key Results BU10119 alone was without any antinociceptive activity. BU10119 (1mg/kg) was able to block U50,488, buprenorphine and morphine induced antinociception. The kappa antagonist effects of BU10119 in the tail-withdrawal assay reversed between 24-48h. BU10119 was without significant locomotor or rewarding effects. BU10119 (1mg/kg) significantly reduced the latency to feed in the novelty-induced hypophagia task and reduced immobility time in the forced swim test, compared to saline treated animals. There were no significant effects of BU10119 in either the elevated plus maze or the light dark box. Both acute and repeated restraint stress-induced analgesia was blocked by pretreatment with BU10119 (1mg/kg). Parallel stress-induced increases in plasma corticosterone were not affected. Conclusions and Implications BU10119 is a mixed mu/kappa opioid receptor antagonist with relatively short-duration kappa antagonist activity. Based on these preclinical data, BU10119 has therapeutic potential in the treatment of depression and other stress-induced conditions.

Endogenous opioid system dysregulation in depression: implications for new therapeutic approaches

Abstract: The United States is in the midst of an opioid addiction and overdose crisis precipitated and exacerbated by use of prescription opioid medicines. The majority of opioid prescriptions are dispensed to patients with comorbid mood disorders including major depressive disorder (MDD). A growing body of research indicates that the endogenous opioid system is directly involved in the regulation of mood and is dysregulated in MDD. This involvement of the endogenous opioid system may underlie the disproportionate use of opioids among patients with mood disorders. Emerging approaches to address endogenous opioid dysregulation in MDD may yield novel therapeutics that have a low or absent risk of abuse and addiction relative to µ-opioid agonists. Moreover, agents targeting the endogenous opioid system would be expected to yield clinical benefits qualitatively different from conventional monaminergic antidepressants. The development of safe and effective agents to treat MDD-associated endogenous opioid dysregulation may represent a distinct and currently underappreciated means of addressing treatment resistant depression with the potential to attenuate the on-going opioid crisis.

Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials.

Abstract: Kappa-opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anxiety, and substance abuse disorders. A general ability to mitigate the effects of stress, which can trigger or exacerbate these conditions, may explain their putative efficacy across such a broad array of conditions. The discovery of their potentially therapeutic effects evolved from preclinical research designed to characterize the molecular mechanisms by which experience causes neuroadaptations in the nucleus accumbens (NAc), a key element of brain reward circuitry. This research established that exposure to drugs of abuse or stress increases the activity of the transcription factor CREB (cAMP response element binding protein) in the NAc, which leads to elevated expression of the opioid peptide dynorphin, which in turn causes core signs of depressive- and anxiety-related disorders. Disruption of KORs—the endogenous receptors for dynorphin—produces antidepressant- and anxiolytic-like actions in screening procedures that identify standard drugs of these classes, and reduces stress effects in tests used to study addiction and stress-related disorders. Although interest in this target is high, prototypical KOR antagonists have extraordinarily persistent pharmacodynamic effects that complicate clinical trials. The development of shorter-acting KOR antagonists together with more rapid designs for clinical trials may soon provide insight on whether these drugs are efficacious as would be predicted by preclinical work. If successful, KOR antagonists would represent a unique example in psychiatry where the therapeutic mechanism of a drug class is understood before it is shown to be efficacious in humans.