Effects of the triple monoamine uptake inhibitor amitifadine on pain-related depression of behavior and mesolimbic dopamine release in rats

Miller, Laurence L.; Leitl, Michael; Banks, Matthew L.; Blough, Bruce E.; Negus, S. Stevens

doi:10.1016/j.pain.0000000000000018

Cited by 31 publications

(36 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In support of a connection between pain behaviors and reduced dopamine signaling, we recently reported that an acute noxious stimulus sufficient to depress ICSS (intraperitoneal administration of dilute acid) also depressed mesolimbic dopamine release in the nucleus accumbens of rats. Moreover, pain-related depression of both ICSS and dopamine release could be blocked not only by opioid and NSAID analgesics, but also by the novel “triple” uptake inhibitor amitifadine (Leitl et al, 2014a; Miller et al, 2015b). The present results with bupropion are consistent with the working hypothesis that chronic pain-related depression of behavior produced by a neuropathy manipulation may also be associated with a decrease in dopamine signaling and may be responsive to treatment with drugs that block dopamine transporters.…”

Section: Discussionmentioning

confidence: 99%

“…Bupropion is a dopamine/norepinephrine uptake inhibitor used clinically as an antidepressant and smoking-cessation treatment (Foley et al, 2006; Moreira, 2011). We have reported previously that pain-related depression of ICSS may be mediated by a depression of mesolimbic DA signaling in nucleus accumbens, and monoamine uptake inhibitors like bupropion can block acute acid-induced depression of both ICSS and nucleus accumbens DA levels (Miller et al, 2015b; Rosenberg et al, 2013). Chronic pain may also involve depressed mesolimbic dopaminergic function (Wood, 2008), and bupropion has been reported to alleviate neuropathic pain clinically (Semenchuk et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacological modulation of neuropathic pain-related depression of behavior: effects of morphine, ketoprofen, bupropion and ∆9-tetrahydrocannabinol on formalin-induced depression of intracranial self-stimulation in rats

Leitl

Negus

2016

Behavioural Pharmacology

Self Cite

View full text Add to dashboard Cite

Neuropathic pain is often associated with behavioral depression. Intraplantar formalin produces sustained, neuropathy-associated depression of intracranial self-stimulation (ICSS) in rats. This study evaluated pharmacological modulation of formalin-induced ICSS depression. Rats with intracranial electrodes targeting the medial forebrain bundle responded for electrical brain stimulation in an ICSS procedure. Bilateral intraplantar formalin administration depressed ICSS for 14 days. Morphine (0.32–3.2 mg/kg), ketoprofen (0.1–10 mg/kg), bupropion (3.2–32 mg/kg), and Δ9-tetrahydrocannabinol (THC; 0.32–3.2 mg/kg) were evaluated for their effectiveness to reverse formalin-induced depression of ICSS. Drug effects on formalin-induced mechanical allodynia were evaluated for comparison. Morphine and bupropion reversed both formalin-induced ICSS depression and mechanical allodynia, and effects on ICSS were sustained during repeated treatment. Ketoprofen failed to reverse either formalin effect. THC blocked mechanical allodynia, but decreased ICSS in control rats and exacerbated formalin-induced depression of ICSS. The failure of ketoprofen to alter formalin effects suggests that formalin effects result from neuropathy rather than inflammation. The effectiveness of morphine and bupropion to reverse formalin effects agrees with other evidence that these drugs block pain-depressed behavior in rats and relieve neuropathic pain in humans. The effects of THC suggest general behavioral suppression and do not support the use of THC to treat neuropathic pain.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacological modulation of neuropathic pain-related depression of behavior: effects of morphine, ketoprofen, bupropion and ∆9-tetrahydrocannabinol on formalin-induced depression of intracranial self-stimulation in rats

Leitl

Negus

2016

Behavioural Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…At the completion of all experiments, rats were euthanized with CO 2 , and brains were removed and stored in 10% formalin. Probe placement was verified by visual inspection of cannula tracks in unstained brain sections as described previously (Bert et al, 2004;Miller et al, 2015). Only rats with correct probe placements were included in data analyses (data from n 5 9 rats were discarded due to improper cannula placement).…”

Section: Microdialysismentioning

confidence: 99%

Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin

Suyama

Sakloth

Kolanoś

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Methcathinone (MCAT) is a monoamine releaser and parent compound to a new class of designer drugs that includes the synthetic cathinones mephedrone and flephedrone. Using MCAT and a series of para-substituted (or 4-substituted) MCAT analogs, it has been previously shown that expression of abuserelated behavioral effects in rats correlates both with the volume of the para substituent and in vitro neurochemical selectivity to promote monoamine release via the dopamine (DA) versus serotonin (5-HT) transporters in rat brain synaptosomes. The present study used in vivo microdialysis to determine the relationship between these previous measures and the in vivo neurochemical selectivity of these compounds to alter nucleus accumbens (NAc) DA and 5-HT levels. Male Sprague-Dawley rats were implanted with bilateral guide cannulae targeting the NAc. MCAT and five para-substituted analogs (4-F, 4-Cl, 4-Br, 4-CH 3, and 4-OCH 3 ) produced dose-and time-dependent increases in NAc DA and/or 5-HT levels. Selectivity was determined as the dose required to increase peak 5-HT levels by 250% divided by the dose required to increase peak DA levels by 250%. This measure of in vivo neurochemical selectivity varied across compounds and correlated with 1) in vivo expression of abuse-related behavioral effects (r 5 0.89, P 5 0.02); 2) in vitro selectivity to promote monoamine release via DA and 5-HT transporters (r 5 0.95, P , 0.01); and 3) molecular volume of the para substituent (r 5 20.85, P 5 0.03). These results support a relationship between these molecular, neurochemical, and behavioral measures and support a role for molecular structure as a determinant of abuse-related neurochemical and behavioral effects of MCAT analogs.

show abstract

“…Antidepressant treatments that include DAT inhibition, including triple reuptake inhibitors (TRIs) that combine inhibition of SERT and NET with DAT, are being developed because of their expected higher efficacy in treating depression. 12,14-16 The classical inhibitors of DAT, such as methylphenidate, are being considered as co-therapy for treating depression, but there is a risk of side effects, such as inducing mania in patients with bipolar disorder. 17 However, an allosteric inhibitor of DAT that has a more subtle action might have an advantage over stimulant drugs that are orthosteric DAT inhibitors in the treatment of behavioral disorders associated with DA deficiency.…”

Section: Introductionmentioning

confidence: 99%

Scaffold Repurposing of Nucleosides (Adenosine Receptor Agonists): Enhanced Activity at the Human Dopamine and Norepinephrine Sodium Symporters

et al. 2017

View full text Add to dashboard Cite

We have repurposed (N)-methanocarba adenosine derivatives (A3 adenosine receptor (AR) agonists) to enhance radioligand binding allosterically at the human dopamine (DA) transporter (DAT) and inhibit DA uptake. We extended the structure-activity relationship of this series with small N6-alkyl substitution, 5′-esters, deaza modifications of adenine, and ribose restored in place of methanocarba. C2-(5-halothien-2-yl)-ethynyl 5′-methyl 9 (MRS7292) and 5′-ethyl 10 (MRS7232) esters enhanced binding at DAT (EC50 ∼35 nM) and at norepinephrine transporter (NET). 9 and 10 were selective for DAT compared to A3AR in the mouse, but not human. At DAT, binding of two structurally dissimilar radioligands was enhanced; NET binding of only one radioligand was enhanced; SERT radioligand binding was minimally affected. 10 was more potent than cocaine at inhibiting DA uptake (IC50 = 107 nM). Ribose analogues were weaker in DAT interaction than corresponding bicyclics. Thus, we enhanced the neurotransmitter transporters activity of rigid nucleosides while reducing A3AR affinity.

show abstract

Effects of the triple monoamine uptake inhibitor amitifadine on pain-related depression of behavior and mesolimbic dopamine release in rats

Cited by 31 publications

References 53 publications

Pharmacological modulation of neuropathic pain-related depression of behavior: effects of morphine, ketoprofen, bupropion and ∆9-tetrahydrocannabinol on formalin-induced depression of intracranial self-stimulation in rats

Pharmacological modulation of neuropathic pain-related depression of behavior: effects of morphine, ketoprofen, bupropion and ∆9-tetrahydrocannabinol on formalin-induced depression of intracranial self-stimulation in rats

Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin

Scaffold Repurposing of Nucleosides (Adenosine Receptor Agonists): Enhanced Activity at the Human Dopamine and Norepinephrine Sodium Symporters

Contact Info

Product

Resources

About