Tramadol and another atypical opioid meperidine have exaggerated serotonin syndrome behavioural effects, but decreased analgesic effects, in genetically deficient serotonin transporter (SERT) mice

Abstract

The serotonin syndrome is a potential side effect of serotonin-enhancing drugs, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs). We recently reported a genetic mouse model for the serotonin syndrome, as serotonin transporter (SERT)-deficient mice have exaggerated serotonin syndrome behavioral responses to the MAOI tranylcypromine and the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP). As numerous case reports implicate the atypical opioids tramadol and meperidine in the development of the human serotonin syndrome, we examined tramadol and meperidine as possible causative drugs in the rodent model of the serotonin syndrome in SERT wildtype (+/+), heterozygous (+/−) and knockout (−/−) mice. Comparisons were made to SERT mice treated with either vehicle or morphine, an opioid not implicated in the serotonin syndrome in humans. Here we show that tramadol and meperidine, but not morphine, induce serotonin syndrome-like behaviors in mice, and we show that this response is exaggerated in mice lacking one or two copies of SERT. The exaggerated response to tramadol in SERT −/− mice was blocked by pretreatment with the 5-HT1A antagonist WAY 100635. Further, we show that morphine-, meperidine- and tramadol-induced analgesia is markedly decreased in SERT −/− mice. These studies suggest that caution seems warranted in prescribing or not warning patients receiving SSRIs or MAOIs, that dangerous side effects may occur during concurrent use of tramadol and similar agents. These findings suggest that it is conceivable that there might be increased vulnerability in individuals with SERT polymorphisms that may reduce SERT by more than 50%, the level in SERT +/− mice.

Monoamine Transporters

“…Complete loss of functional SERT caused spontaneous serotonin syndrome-like behaviors (tremor, Straub tail and backward movement) and hypersensitivity to its induction by serotonergic or opioid drugs, reduced motor coordination, strength, and locomotor activity, an anxiety-like and depressive-like phenotype and decreased aggression and other social interactions (214-227). In agreement with the large literature implicating 5-HT in the pathophysiology and treatment of mood and anxiety disorders, SERT-deficient (−/− and +/-) mice showed an anxiogenic phenotype, which was ameliorated by a 5-HT1A antagonist (215, 220, 228, 229). Cognitive assays showed SERT−/− rodents may perform better in emotionally guided/motivated learning, but worse in “neutral” tasks - perhaps related to the anxiety-like phenotype (230, 231).…”

Monoaminergic Antidepressants in the Relief of Pain: Potential Therapeutic Utility of Triple Reuptake Inhibitors (TRIs)

“…Although the spontaneous pain sensitivity is unaltered in these mutant mice compared to their wild-type littermates [221], multiple sources of evidence suggest that the pharmacological blockade of 5-HTT induced by SSRIs reduces acute pain in the hotplate and tail flick tests (Table 3). For example, citalopram produces antinociceptive effects in both rats [222-224] and mice [219,225].…”

Mutations in monoamine oxidase (MAO) genes in mice lead to hypersensitivity to serotonin-enhancing drugs: implications for drug side effects in humans

“…Animals were placed in a large Plexiglass cylinder and after 15 min of habituation were administered 5-HTP (80 mg kg −1 ) 18,19 or its vehicle in the first experiment and tramadol (60 mg kg −1 ) 33 or its vehicle in the second experiment. Behavioral assessments were made based on previous methods.…”

“…31,32 We previously showed that SERT-KO mice display increased baseline levels of serotonin syndrome behaviors, 19,33,34 in addition to further exaggerated behavioral responses following the MAOA/B inhibitor tranylcypromine, 19 5-HTP 18,32,35 and the atypical opioids tramadol and meperidine, 33 each when administered alone.…”