Effects of chronic doxepin and amitriptyline administration in naïve mice and in neuropathic pain mice model

Mika, Joanna; Jurga, Agnieszka M.; Starnowska, Joanna; Wasylewski, Mateusz; Rojewska, Ewelina; Makuch, Wioletta; Kwiatkowski, Klaudia; Małek, Natalia; Przewłocka, Barbara

doi:10.1016/j.neuroscience.2015.03.003

Cited by 23 publications

(12 citation statements)

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“…41,42 We used all these drugs at a single dose, selected in conformity with previous reports. 16,35,40–44 In the CFA model of chronic inflammatory pain, all drugs were equally effective in increasing mechanical pain thresholds, but only in mice treated with LAC the analgesic effect was still observed after one or two weeks of drug withdrawal. In the CCI model, pregabalin and amitryptiline displayed the greatest efficacy in causing analgesia, as expected by their first-line indication in the treatment of neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

Analgesia induced by the epigenetic drug, L-acetylcarnitine, outlasts the end of treatment in mouse models of chronic inflammatory and neuropathic pain

et al. 2017

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BackgroundL-acetylcarnitine, a drug marketed for the treatment of chronic pain, causes analgesia by epigenetically up-regulating type-2 metabotropic glutamate (mGlu2) receptors in the spinal cord. Because the epigenetic mechanisms are typically long-lasting, we hypothesized that analgesia could outlast the duration of L-acetylcarnitine treatment in models of inflammatory and neuropathic pain.ResultsA seven-day treatment with L-acetylcarnitine (100 mg/kg, once a day, i.p.) produced an antiallodynic effect in the complete Freund adjuvant mouse model of chronic inflammatory pain. L-Acetylcarnitine-induced analgesia persisted for at least 14 days after drug withdrawal. In contrast, the analgesic effect of pregabalin, amitryptiline, ceftriaxone, and N-acetylcysteine disappeared seven days after drug withdrawal. L-acetylcarnitine treatment enhanced mGlu2/3 receptor protein levels in the dorsal region of the spinal cord. This effect also persisted for two weeks after drug withdrawal and was associated with increased levels of acetylated histone H3 bound to the Grm2 gene promoter in the dorsal root ganglia. A long-lasting analgesic effect of L-acetylcarnitine was also observed in mice subjected to chronic constriction injury of the sciatic nerve. In these animals, a 14-day treatment with pregabalin, amitryptiline, tramadol, or L-acetylcarnitine produced a significant antiallodynic effect, with pregabalin displaying the greatest efficacy. In mice treated with pregabalin, tramadol or L-acetylcarnitine the analgesic effect was still visible 15 days after the end of drug treatment. However, only in mice treated with L-acetylcarnitine analgesia persisted 37 days after drug withdrawal. This effect was associated with an increase in mGlu2/3 receptor protein levels in the dorsal horns of the spinal cord.ConclusionsOur findings suggest that L-acetylcarnitine has the unique property to cause a long-lasting analgesic effect that might reduce relapses in patients suffering from chronic pain.

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Section: Discussionmentioning

confidence: 99%

Analgesia induced by the epigenetic drug, L-acetylcarnitine, outlasts the end of treatment in mouse models of chronic inflammatory and neuropathic pain

et al. 2017

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“…Von Frey's Test Mechanical tactile hypersensitivity in CCI mice was measured on the 7th and 14th day after CCI using a series of von Frey filaments (Stoelting, Wood Dale, IL, USA), ranging from 0.6 to 6 g (Mika et al, 2015). Animals were placed in plastic cages with a wire-mesh floor, allowing them to move freely.…”

Section: Behavioral Testsmentioning

confidence: 99%

“…In naive mice, the reaction of any hind paw was noted. The cut-off latency for this test was 30 s (Mika et al, 2015).…”

Section: Behavioral Testsmentioning

confidence: 99%

“…To assess the effects of longer-lasting pain, which could affect striatal gene transcription more profoundly, qRT-PCR measurements were performed 14 days after CCI; the measures of neuropathic pain, tactile, and thermal hypersensitivity remain at comparable levels between days 7 and 14 after CCI in mice ( Fig. 1; Mika et al 2009Mika et al , 2015Rojewska et al 2018). Extracts of the whole NAc were used for this analysis.…”

Section: The Influence Of CCI On Opioid Propeptide Gene Expression Inmentioning

confidence: 99%

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Neuropathic Pain Dysregulates Gene Expression of the Forebrain Opioid and Dopamine Systems

et al. 2020

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Disturbances in the function of the mesostriatal dopamine system may contribute to the development and maintenance of chronic pain, including its sensory and emotional/cognitive aspects. In the present study, we assessed the influence of chronic constriction injury (CCI) of the sciatic nerve on the expression of genes coding for dopamine and opioid receptors as well as opioid propeptides in the mouse mesostriatal system, particularly in the nucleus accumbens. We demonstrated bilateral increases in mRNA levels of the dopamine D1 and D2 receptors (the latter accompanied by elevated protein level), opioid propeptides proenkephalin and prodynorphin, as well as delta and kappa (but not mu) opioid receptors in the nucleus accumbens at 7 to 14 days after CCI. These results show that CCI-induced neuropathic pain is accompanied by a major transcriptional dysregulation of molecules involved in dopaminergic and opioidergic signaling in the striatum/nucleus accumbens. Possible functional consequences of these changes include opposite effects of upregulated enkephalin/delta opioid receptor signaling vs. dynorphin/ kappa opioid receptor signaling, with the former most likely having an analgesic effect and the latter exacerbating pain and contributing to pain-related negative emotional states.

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“…If one considers the picture emerged from a more precise dissection of the nociceptive circuitries in the substantia gelatinosa of the spinal cord (Figure2), amitriptyline has the potential to target at the same time a pro-(BDNF) and an antinociceptive (GDNF) factor at this very important relay station. Notably, a very recent study has shown that systemic (intraperitoneal) amitriptyline reversed the effects of allodynia and hyperalgesia induced by chronic constriction injury (CCI) in mice [93], and case reports in the clinical literature indicate that high doses of topical amitriptyline are beneficial in the treatment of neuropathic pain although systemic adverse effects should be taken into account [94] .…”

Section: An Interesting Option For Developing New Drugs Is Thus Targementioning

confidence: 99%

Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain

Merighi

2015

Expert Opinion on Therapeutic Targets

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Introduction: GDNF and its family of ligands (GFLs) have several functions in the nervous system. As a survival factor for dopaminergic neurons, GDNF was used in clinical trials for Parkinson's disease. However, GFLs their receptors are potential targets for new pain-controlling drugs. Such a potential should not be underestimated because molecules with analgesic activities in rodents mostly failed to be effective in translational studies. Areas covered:The circuitry, molecular and cellular mechanisms by which GFLs control nociception, their intervention in inflammatory and neuropathic pain, the problems related to effective GDNF delivery to the brain, the possibility to target the GFL receptor complex rather than its ligands, also by the use of non-peptidyl agonists, are discussed. Expert opinion:In nociceptive pathways, an ideal drug should either: i. Target the release of endogenous GFLs from large dense-cored vesicles (LGVs) by acting e.g. onto the phosphatidylinositol-3-phosphate [PtdIns(3)P] pool, which is sensitive to Ca 2+ modulation; ii. Target the GFL receptor complex. Besides to XIB403, a thiol molecule that enhances GFRα family receptor signaling, existing drugs such as retinoic acid and amitriptyline should be considered for effective targeting of GDNF, at least in neuropathic pain. The approach of pain modeling in experimental animals is discussed.

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Effects of chronic doxepin and amitriptyline administration in naïve mice and in neuropathic pain mice model

Cited by 23 publications

References 75 publications

Analgesia induced by the epigenetic drug, L-acetylcarnitine, outlasts the end of treatment in mouse models of chronic inflammatory and neuropathic pain

Analgesia induced by the epigenetic drug, L-acetylcarnitine, outlasts the end of treatment in mouse models of chronic inflammatory and neuropathic pain

Neuropathic Pain Dysregulates Gene Expression of the Forebrain Opioid and Dopamine Systems

Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain

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