Opioid-like adverse effects of tianeptine in male rats and mice

Baird, Tyson R; Akbarali, Hamid I.; Dewey, William L.; Elder, Harrison; Kang, Minho; Marsh, Samuel; Peace, Michelle R.; Poklis, Justin L.; Santos, Edna J.; Negus, S. Stevens

doi:10.1007/s00213-022-06093-w

Cited by 11 publications

(20 citation statements)

References 47 publications

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“…Tianeptine was included in this study as a putative high MOR efficacy comparator, and results are consistent with other recent studies to indicate that tianeptine functions as a low‐potency, high‐efficacy MOR/DOR agonist 22–24 . Insofar as DOR activation has been linked to antidepressant effects, 34,35 these findings support the proposition that clinical antidepressant effects of tianeptine may involve DOR as well as MOR effects.…”

Section: Discussionsupporting

confidence: 88%

“…Effects of the chiral C9-substituted phenylmorphans were compared to effects of tianeptine, an antidepressant drug approved for use in Europe and recently discovered to be a high-efficacy MOR agonist. [22][23][24] Our results confirm and extend previous work with these compounds and identify a set of selective MOR agonists with graded sub-buprenorphine efficacies that could be useful both as candidate therapeutics and as tools to examine the role of MOR efficacy as a determinant of therapeutic and undesirable MOR agonist effects.…”

Section: Introductionsupporting

confidence: 84%

Section: Tianeptinementioning

confidence: 99%

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Role of efficacy as a determinant of locomotor activation by mu‐opioid receptor (MOR) ligands in female and male mice. II. Effects of novel MOR‐selective phenylmorphans with high‐to‐low MOR efficacy

Santos

Nassehi

Bow³

et al. 2023

Pharmacology Res & Perspec

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Low‐efficacy mu‐opioid receptor (MOR) agonists represent promising therapeutics, but existing compounds (e.g., buprenorphine, nalbuphine) span a limited range of low MOR efficacies and have poor MOR selectivity. Accordingly, new and selective low‐efficacy MOR agonists are of interest. A novel set of chiral C9‐substituted phenylmorphans has been reported to display improved MOR selectivity and a range of high‐to‐low MOR efficacies under other conditions; however, a full opioid receptor binding profile for these drugs has not been described. Additionally, studies in mice will be useful for preclinical characterization of these novel compounds, but the pharmacology of these drugs in mice has also not been examined. Accordingly, the present study characterized the binding selectivity and in vitro efficacy of these compounds using assays of opioid receptor binding and ligand‐stimulated [35S]GTPɣS binding. Additionally, locomotor effects were evaluated as a first step for in vivo behavioral assessment in mice. The high‐efficacy MOR agonist and clinically effective antidepressant tianeptine was included as a comparator. In binding studies, all phenylmorphans showed improved MOR selectivity relative to existing lower‐efficacy MOR agonists. In the ligand‐stimulated [35S]GTPɣS binding assay, seven phenylmorphans had graded levels of sub‐buprenorphine MOR efficacy. In locomotor studies, the compounds again showed graded efficacy with a rapid onset and ≥1 h duration of effects, evidence for MOR mediation, and minor sex differences. Tianeptine functioned as a high‐efficacy MOR agonist. Overall, these in vitro and in vivo studies support the characterization of these compounds as MOR‐selective ligands with graded MOR efficacy and utility for further behavioral studies in mice.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionsupporting

confidence: 84%

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Role of efficacy as a determinant of locomotor activation by mu‐opioid receptor (MOR) ligands in female and male mice. II. Effects of novel MOR‐selective phenylmorphans with high‐to‐low MOR efficacy

Santos

Nassehi

Bow³

et al. 2023

Pharmacology Res & Perspec

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“…Data shown are means ± SEM; n = 5 experiments performed in duplicate. (Samuels et al, 2017), the respiratory depressant effects of tianeptine as a μ-receptor agonist have only been assessed recently (Baird et al, 2022). SR-17018 was described as a G protein-biased agonist that acted as an effective analgesic with no significant respiratory depression when administered i.p.…”

Section: Discussionmentioning

confidence: 99%

“…Tianeptine is a low affinity μ‐receptor agonist with established clinical efficacy as an antidepressant at low doses (Gassaway et al, 2014 ; Samuels et al, 2017 ). While its analgesic, antidepressant, locomotor and hypophagic effects were shown to be mediated by the μ‐receptor (Samuels et al, 2017 ), the respiratory depressant effects of tianeptine as a μ‐receptor agonist have only been assessed recently (Baird et al, 2022 ). SR‐17018 was described as a G protein‐biased agonist that acted as an effective analgesic with no significant respiratory depression when administered i.p.…”

Section: Discussionmentioning

confidence: 99%

Assessment of the potential of novel and classical opioids to induce respiratory depression in mice

Hill,

Sanchez,

Lemel

et al. 2023

British J Pharmacology

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AIMSOpioid‐induced respiratory depression limits the use of mu‐opioid receptor agonists in clinical settings and is the main cause of opioid overdose fatalities. The relative potential of different opioid agonists to induce respiratory depression at doses exceeding those producing analgesia is understudied despite its relevance to assessments of opioid safety. Here we evaluated the respiratory depressant and anti‐nociceptive effects of three novel opioids and relate these measurements to their in vitro efficacy.METHODSRespiration was measured in awake, freely moving male mice using whole body plethysmography. Anti‐nociception was measured using the hot plate test. Morphine, oliceridine, and tianeptine were administered intraperitoneally, whereas methadone, oxycodone, and SR‐17018 were administered orally. Receptor activation and arrestin‐3 recruitment were measured in HEK293 cells using BRET assays.RESULTSAcross the dose ranges examined, all opioids in this study depressed respiration in a dose‐dependent manner, with a similar effect at the highest dose, and with tianeptine and oliceridine showing reduced duration of effect compared to morphine, oxycodone, methadone, and SR‐17018. When administered at doses that induced similar respiratory depression, all opioids induced similar anti‐nociception, with tianeptine and oliceridine again showing reduced duration of effect. These data are consistent with the in vitro agonist activity of all the tested compounds.CONCLUSIONSOur data show that in addition to providing effective anti‐nociception, the novel opioids, oliceridine, tianeptine, and SR‐17018 depress respiration in male mice. However, the different potencies and kinetics of effect between these novel opioids may be relevant to their therapeutic application in different clinical settings.

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Tianeptine, an Antidepressant with Opioid Agonist Effects: Pharmacology and Abuse Potential, a Narrative Review

Edinoff,

Sall,

Beckman

et al. 2023

Pain Ther

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Tianeptine is an antidepressant drug approved for the treatment of major depressive disorder in countries other than the US. It is classified as an atypical tricyclic antidepressant and has shown potential benefits in addressing anxiety and irritable bowel disease. However, it is important to note that tianeptine is not approved for any use by the United States Federal Drug Administration (FDA). Despite its lack of approval by the FDA, tianeptine has been distributed online and at small retail locations. The term “gas station drugs” refers to a wide range of substances typically available for purchase from gas stations, corner stores, bodegas, mini marts, smoke shops, and the Internet. These substances may be produced commercially by drug manufacturers or in clandestine laboratories to mimic the effects of more well-known illicit/controlled substances such as marijuana, cocaine, opioids, etc. Tianeptine has made its way to convenience stores and gas station shelves, branded as “Zaza” and “Tianna Red.” It can also be obtained online from independent vendors without a prescription. Misuse of tianeptine can lead to euphoric, opioid-like highs with the potential for chronic users to develop dependence and tolerance. Overdose and use in suicide attempts have also been documented. This manuscript is a narrative review, highlighting the dangers of tianeptine and other gas station drugs and underscoring the urgent need to regulate these substances.

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Opioid-like adverse effects of tianeptine in male rats and mice

Cited by 11 publications

References 47 publications

Role of efficacy as a determinant of locomotor activation by mu‐opioid receptor (MOR) ligands in female and male mice. II. Effects of novel MOR‐selective phenylmorphans with high‐to‐low MOR efficacy

Role of efficacy as a determinant of locomotor activation by mu‐opioid receptor (MOR) ligands in female and male mice. II. Effects of novel MOR‐selective phenylmorphans with high‐to‐low MOR efficacy

Assessment of the potential of novel and classical opioids to induce respiratory depression in mice

Tianeptine, an Antidepressant with Opioid Agonist Effects: Pharmacology and Abuse Potential, a Narrative Review

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