Antihyperalgesic effect of duloxetine and amitriptyline in rats after peripheral nerve injury: Influence of descending noradrenergic plasticity

Hoshino, Hiromitsu; Obata, Hideaki; Saito, Shigeru

doi:10.1016/j.neulet.2015.06.041

Cited by 27 publications

(28 citation statements)

References 19 publications

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“…The main purpose of the present investigation was to demonstrate this claim in patients with CLBP. These conditions are associated with dysfunction of endogenous pain modulation and associated with diminished conditioned pain modulation, and it is highly likely that duloxetine, by enhancing noradrenergic and serotonergic neurotransmission, engages descending pain modulatory systems, and may normalize this dysfunctional process 28,29…”

Section: Discussionmentioning

confidence: 99%

Assessment of direct analgesic effect of duloxetine for chronic low back pain: post hoc path analysis of double-blind, placebo-controlled studies

Enomoto

Fujikoshi

Funai³

et al. 2017

JPR

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BackgroundComorbid depression and depressive symptoms are common in patients with chronic low back pain (CLBP). Duloxetine is clinically effective in major depressive disorder and several chronic pain states, including CLBP. The objective of this post hoc meta-analysis was to assess direct and indirect analgesic efficacy of duloxetine for patients with CLBP in previous clinical trials.MethodsPost hoc path analyses were conducted of 3 randomized, double-blind, clinical studies of patients receiving duloxetine or placebo for CLBP. The primary outcome measure for pain was the Brief Pain Inventory, average pain score. A secondary outcome measure, the Beck Depression Inventory-II, was used for depressive symptoms. The changes in score from baseline to endpoint were determined for each index. Path analyses were employed to calculate the proportion of analgesia that may be attributed to a direct effect of duloxetine on pain.ResultsA total of 851 patients (400 duloxetine and 451 placebo) were included in this analysis. Duloxetine significantly improved pain scores compared with placebo (p<0.001). It also significantly improved depressive scores compared with placebo (p=0.015). Path analyses showed that 91.1% of the analgesic effect of duloxetine could be attributed to a direct analgesic effect, and 8.9% to its antidepressant effect. Similar results were obtained when data were evaluated at weeks 4 and 7, and when patients were randomized to subgroups based on baseline pain scores, baseline depressive symptoms scores, and gender.ConclusionDuloxetine significantly improved pain in patients with CLBP. Path analyses results suggest that duloxetine produced analgesia mainly through mechanisms directly impacting pain modulation rather than lifting depressive symptoms. This effect was consistent across all subgroups tested.

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Section: Discussionmentioning

confidence: 99%

Assessment of direct analgesic effect of duloxetine for chronic low back pain: post hoc path analysis of double-blind, placebo-controlled studies

Enomoto

Fujikoshi

Funai³

et al. 2017

JPR

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“…Studies have shown that duloxetine has attenuating effects on pain hypersensitivity in models of neuropathic pain associated with traumatic nerve injury [ 32 , 33 , 34 , 35 ], diabetic neuropathy [ 36 , 37 ] and fibromyalgia [ 38 ]. In addition to its clinical use for depression, duloxetine is frequently used for treating chronic pain such as diabetic neuropathic pain [ 39 , 40 ], chronic low back pain [ 41 , 42 ], osteoarthritis [ 41 , 43 ] and fibromyalgia [ 41 , 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

Duloxetine Inhibits Microglial P2X4 Receptor Function and Alleviates Neuropathic Pain after Peripheral Nerve Injury

et al. 2016

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P2X4 receptors (P2X4R) are a family of ATP-gated non-selective cation channels. We previously demonstrated that activation of P2X4R in spinal microglia is crucial for neuropathic pain, a highly debilitating chronic pain condition, suggesting that P2X4R is a potential therapeutic target for treating neuropathic pain. Thus, the identification of a compound that has a potent inhibitory effect on P2X4R is an important clinical challenge. In the present study, we screened a chemical library of clinically approved drugs and show for the first time that duloxetine, a serotonin and noradrenaline reuptake inhibitor, has an inhibitory effect on rodent and human P2X4R. In primary cultured microglial cells, duloxetine also inhibited P2X4R-, but not P2X7R-, mediated responses. Moreover, intrathecal administration of duloxetine in a model of neuropathic pain produced a reversal of nerve injury-induced mechanical allodynia, a cardinal symptom of neuropathic pain. In rats that were pretreated with a serotonin-depleting agent and a noradrenaline neurotoxin, the antiallodynic effect of duloxetine was reduced, but still remained. Based on these results, we suggest that, in addition to duloxetine’s primary inhibitory action on serotonin and noradrenaline transporters, an inhibitory effect on P2X4R may be involved at least in part in an antiallodynic effect of intrathecal duloxetine in a model of neuropathic pain.

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“…We next tested another way to elevate NE level in the brain for treatment of PD-associated pain by using duloxetine, which is a NE and 5-HT reuptake inhibitor. Duloxetine was shown to be effective for the treatment of neuropathic pain [ 61 , 62 ]. In our study, systemic injection of duloxetine significantly inhibited pain hypersensitivity in 6-OHDA-lesioned rats at the 5th week after surgery.…”

Section: Discussionmentioning

confidence: 99%

Restoring Spinal Noradrenergic Inhibitory Tone Attenuates Pain Hypersensitivity in a Rat Model of Parkinson’s Disease

et al. 2016

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In the present study, we investigated whether restoring descending noradrenergic inhibitory tone can attenuate pain in a PD rat model, which was established by stereotaxic infusion of 6-hydroxydopamine (6-OHDA) into the bilateral striatum (CPu). PD rats developed thermal and mechanical hypersensitivity at the 4th week after surgery. HPLC analysis showed that NE content, but not dopamine or 5-HT, significantly decreased in lumbar spinal cord in PD rats. Additional noradrenergic depletion by injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) aggravated pain hypersensitivity in PD rats. At the 5th week after injection of 6-OHDA, systemic treatment with pharmacological norepinephrine (NE) precursor droxidopa (L-DOPS) or α2 adrenoceptor agonist clonidine significantly attenuated thermal and mechanical pain hypersensitivity in PD rats. Furthermore, application of norepinephrine (NE) and 5-hydroxytryptamine (5-HT) reuptake inhibitors duloxetine, but not 5-HT selective reuptake inhibitors sertraline, significantly inhibited thermal and mechanical pain hypersensitivity in PD rats. Systemic administration of Madopar (L-DOPA) or the D2/D3 agonist pramipexole slightly inhibited the thermal, but not mechanical, hypersensitivity in PD rats. Thus, our study revealed that impairment of descending noradrenergic system may play a key role in PD-associated pain and restoring spinal noradrenergic inhibitory tone may serve as a novel strategy to manage PD-associated pain.

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Antihyperalgesic effect of duloxetine and amitriptyline in rats after peripheral nerve injury: Influence of descending noradrenergic plasticity

Cited by 27 publications

References 19 publications

Assessment of direct analgesic effect of duloxetine for chronic low back pain: post hoc path analysis of double-blind, placebo-controlled studies

Assessment of direct analgesic effect of duloxetine for chronic low back pain: post hoc path analysis of double-blind, placebo-controlled studies

Duloxetine Inhibits Microglial P2X4 Receptor Function and Alleviates Neuropathic Pain after Peripheral Nerve Injury

Restoring Spinal Noradrenergic Inhibitory Tone Attenuates Pain Hypersensitivity in a Rat Model of Parkinson’s Disease

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