Efficacy of Duloxetine, a Potent and Balanced Serotonin-Norepinephrine Reuptake Inhibitor in Persistent Pain Models in Rats

Iyengar, Smriti; Webster, Amy A.; Hemrick‐Luecke, Susan K.; Xu, J.; Simmons, Rosa Maria A.

doi:10.1124/jpet.104.070656

Cited by 271 publications

(194 citation statements)

References 36 publications

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“…8 In agreement with the SERT RO and α-MMT results, we observed a reversal in the formalininduced pain behaviors with an absolute ED 50 of 13.4 mg/kg PO ( Figure 5). Importantly, no neurological effects as measured by the rotorod assay were evident up to the highest dose tested (100 mg/kg) (data not shown).…”

supporting

confidence: 87%

Discovery of a Potent, Dual Serotonin and Norepinephrine Reuptake Inhibitor

Dreyfus

Myers

Badescu

et al. 2013

ACS Med. Chem. Lett.

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The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug−drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions. KEYWORDS: SERT, NET, dual, reuptake inhibitor, SNRI, SERT RO, α-MMT, pain M anipulation of central nervous system (CNS) levels of the neurotransmitters serotonin (5-HT) and norepinephrine (NE), through inhibition of the corresponding reuptake transporters SERT (serotonin transporter) and NET (norepinephrine transporter), has been a successful strategy for treating several CNS disorders including depression, generalized anxiety disorder, and several chronic pain conditions. 1−6 Several compounds that selectively inhibit these transporters (known as serotonin norepinephrine reuptake inhibitors or SNRIs) are available on the market (compounds 5−8, see Figure 1) and have proven to be safe and effective drugs for the treatment of pain and/or mood disorders. However, these molecules often show more potent inhibition of SERT than NET in vitro (Table 1). Published studies have demonstrated that selective SERT and NET inhibitors can show additive or synergistic analgesic efficacy. 7,8 For our targeted indication of pain, we hypothesized that a SNRI that inhibited SERT and NET with comparable potency would lead to a compound with a superior efficacy and safety profile. Therefore, we undertook to develop a new SNRI that, in a single molecule, improved NET activity versus current SNRIs, retained potent and balanced in vivo activity at both transporters, had good brain exposure, was metabolically stable, and provided minimal drug−drug interaction (DDI) risk to patients on other therapies.Our search for a balanced SNRI led to the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Amine containing compounds have long been a fertile source of reuptake inhibitors with a variety of profiles. 9 SNRIs 5−8 all show a similar pharmacophore, with an amine and an aryl group separated by 2−4 sp 3 hybridized atoms. The pyrrolidines we synthesized and tested represent a conformationally constrained version of this general pharmacophore that maintains potent transporter inhibition. 10 Compound 1 contains several innovative features that make it an improvement over earlier scaffolds. The pyrrolidine ring provided the secondary amine that is common to many reuptake inhibitors, but in a novel constrained geometry. Introduction of the pyridine ring, in place of a phenyl ring, was a key change that delivered both our desired pharmacological profile and...

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supporting

confidence: 87%

Discovery of a Potent, Dual Serotonin and Norepinephrine Reuptake Inhibitor

Dreyfus

Myers

Badescu

et al. 2013

ACS Med. Chem. Lett.

Self Cite

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“…If these outcome data will be confirmed in larger series of patients, duloxetine may become a new treatment option for the prophylaxis of these disorders. Duloxetine is a selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor [40]. Duloxetine has been reported to be effective in diabetic neuropathic pain and recently in chronic orofacial pain disorders, such as burning mouth syndrome [41,42], suggesting other mechanisms of action.…”

Section: Discussionmentioning

confidence: 99%

SUNCT and SUNA: medical and surgical treatments

Lambru

Matharu

2013

Neurol Sci

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Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are rare and often disabling primary headache disorders. Their management can be challenging. The abortive therapies are not generally useful as the attacks are relatively short lasting. A myriad of pharmacological preventive treatments have been tried in single case reports or small series in an openlabel fashion. Lamotrigine, as an oral preventive treatment, and lidocaine, as an intravenous transitional treatment, seem to be the most effective therapies. For medically intractable chronic forms of SUNCT and SUNA, several surgical approaches have been tried. These include ablative procedures involving the trigeminal nerve or the Gasserian ganglion, microvascular decompression of the trigeminal nerve, and neurostimulation techniques. This review provides an overview of the current pharmacological and surgical options for SUNCT and SUNA syndromes.

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“…I n h i b i t o r y neurotransmitters increase the transmission in descending neural pathways and thereby decrease the feeling of pain. It is claimed that serotonin and noradrenaline (norepinephrine) increase the activities of these inhibitory neurotransmitters, thus decreasing the sensation of pain; the function of anti-depressants in decreasing pain symptoms supports this view (7)(8)(9)(10).…”

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confidence: 59%

Assessment of pain symptoms experienced in major depressive disorder and anxiety disorder

Koksal¹,

Aslan²,

Yazici³

2017

Dusunen Adam

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Assessment of pain symptoms experienced in major depressive disorder and anxiety disorderObjective: Ever since the important role serotonin plays in the mechanism of pain emergence became known, there has been a heightened interest in examining the pain that accompanies psychiatric disorders. However, the relationship between pain and psychiatric disorders remains unclear. In this study, we aimed to obtain information about the frequency and characteristics of pain seen in patients diagnosed with major depressive disorder (MDD) and anxiety disorder (AD). Method: The Hamilton Rating Scale for Depression (HAM-D), the Hamilton Anxiety Rating Scale (HAM-A), and the "Brief Pain Inventory" (BPI) were administered to 94 patients diagnosed with MDD and 94 patients diagnosed with AD, respectively. Comparisons between the diagnosed groups, pain characteristics and sociodemographic variables were examined using the Chi-square and Mann-Whitney U tests in the statistical software package SPSS 11.0. Spearman's rho test was utilized in order to examine correlation. Results: Pain complaints in the MDD group were found in 55.3% (n=52), while this figure was 52.1% (n=49) in the AD group. There was no difference in the frequency of experiencing pain between the two groups (p>0.05). Variations of age, gender, and employment status did not correlate to differences in the presence of pain in MDD (p>0.05). In the AD group however, while there were no differences in age and gender regarding the presence of pain, complaints were more frequent in patients who did not work (p<0.05). In both groups, with a longer period of education the patients had received, there was a decrease in pain frequency (p<0.05). There was a positive correlation between HAM-D and HAM-A scores and pain intensity (HAM-D rho=0.217, HAM-A rho=-0.088, p<0.05); however, no correlation was found with the number of pain locations (HAM-D rho=0.165, HAM-A rho=0.105, p>0.05). It was found that pain affected self-care negatively in MDD (p<0.05). Conclusion:The frequency of pain experienced in MDD and AD patients whom we assessed with the pain survey form was quite high. Additionally, an important finding was that while there was an increase in the intensity of pain with HAM-D , there was no increase in pain locations. It is important that pain is examined and evaluated as a symptom that can emerge in psychiatric disorders and not just a symptom in relation to physical illness. Keywords: Anxiety disorders, major depressive disorder, mental health, pain ÖZET Majör depresif bozukluk ve anksiyete bozukluklarında görülen ağrı semptomunun değerlendirilmesiAmaç: Serotoninin ağrının ortaya çıkış mekanizmasında önemli etkisi olduğu bilindiğinden bu yana psikiyatrik bozukluklara eşlik eden ağrıya olan ilgi artmıştır. Fakat ağrı ile psikiyatrik bozuklukların ilişkisi henüz net olarak bilinmemektedir. Çalışmamızda majör depresif bozukluk (MDB) ve anksiyete bozukluğu (AB) tanısı olanlarda ağrı sıklığı ve özellikleri konusunda bilgi edinmeyi amaçladık. Yöntem: Doksan dört MDB 94...

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Efficacy of Duloxetine, a Potent and Balanced Serotonin-Norepinephrine Reuptake Inhibitor in Persistent Pain Models in Rats

Cited by 271 publications

References 36 publications

Discovery of a Potent, Dual Serotonin and Norepinephrine Reuptake Inhibitor

Discovery of a Potent, Dual Serotonin and Norepinephrine Reuptake Inhibitor

SUNCT and SUNA: medical and surgical treatments

Assessment of pain symptoms experienced in major depressive disorder and anxiety disorder

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