Antinociceptive effects of tricyclic antidepressants and their noradrenergic metabolites

Rojas-Corrales, M.O.; Casas, J.; Moreno-Brea, M.R.; Gibert-Rahola, J.; Micó, Juan Antonio

doi:10.1016/s0924-977x(03)00017-8

Cited by 31 publications

(22 citation statements)

References 49 publications

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“…that imipramine produces a significant acute analgesic effect at 10-40 mg/kg in the formalin test (Sabetkasai et al, 1999;Zarrindast et al, 2000aZarrindast et al, , 2003, 10-15 mg/kg in the hot-plate test (Ghelardini et al, 2000;Sahebgharani and Zarrindast, 2001), and 20-30 mg/kg against a neuropathic pain-like state (Zarrindast et al, 2000b). It also induces an antidepressive effect at 10-32 mg/kg in the forced swimming test (Clenet et al, 2001;David et al, 2003;Rojas-Corrales et al, 2003). In contrast, some reports have stated that acute administration does not produce an anxiolytic effect (Cole and Rodgers, 1995).…”

Section: Discussionmentioning

confidence: 99%

Usefulness of Antidepressants for Improving the Neuropathic Pain-Like State and Pain-Induced Anxiety through Actions at Different Brain Sites

Matsuzawa-Yanagida

Narita

Nakajima

et al. 2007

Neuropsychopharmacol

121

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Clinically, it is well known that chronic pain induces depression, anxiety, and a reduced quality of life. There have been many reports on the relationship between pain and emotion. We previously reported that chronic pain induced anxiety with changes in opioidergic function in the central nervous system. In this study, we evaluated the anxiolytic-like effects of several types of antidepressants under a chronic neuropathic pain-like state and searched for the brain site of action where antidepressants show anxiolytic or antinociceptive effects. Sciatic nerve-ligated mice exhibited thermal hyperalgesia and tactile allodynia from days 7 to 28 after nerve ligation. At 4 weeks after ligation, these mice showed a significant anxiety-related behavior in the light-dark test and the elevated plus-maze test. Under these conditions, repeated administration of antidepressants, including the tricyclic antidepressant (TCA) imipramine, the serotonin noradrenaline reuptake inhibitor (SNRI) milnacipran, and the selective serotonin reuptake inhibitor (SSRI) paroxetine, significantly prevented the anxiety-related behaviors induced by chronic neuropathic pain. These antidepressants also produced a significant reduction in thermal hyperalgesia and tactile allodynia. Moreover, the microinjection of paroxetine into the basolateral amygdala or cingulate cortex reduced anxiety-related behavior, and microinjection into the primary somatosensory cortex significantly attenuated thermal hyperalgesia. These findings suggest that serotonergic antidepressants are effective for treating anxiety associated with chronic neuropathic pain and may be useful for treating neuropathic pain with emotional dysfunction such as anxiety. Furthermore, SSRIs show anxiolytic and antinociceptive effects by acting on different brain regions.

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Section: Discussionmentioning

confidence: 99%

Usefulness of Antidepressants for Improving the Neuropathic Pain-Like State and Pain-Induced Anxiety through Actions at Different Brain Sites

Matsuzawa-Yanagida

Narita

Nakajima

et al. 2007

Neuropsychopharmacol

121

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“…Amitriptyline has been shown previously to change locomotor activity in rodents attributable to sedation, ataxia, changes in nociception, depression, or anxiety. [45][46][47][48][49] In one study, amitriptyline did not change locomotor activity in the chronic constriction injury model despite reducing allodynia. …”

Section: Effect Of Rufinamide On Mechanical Allodynia After Sni In Micementioning

confidence: 99%

“…45,50 Rufinamide Has the Potential of a New Treatment for Neuropathic Pain As first-line therapy for the treatment of neuropathic pain, clinical guidelines propose tricyclic antidepressants (amitriptyline), serotonin and norepinephrine reuptake inhibitors (duloxetine and venlafaxine) or anticonvulsants targeting α2-δ subunit of calcium channels (gabapentin and pregabalin). 8,51 The most effective antidepressants in the treatment of neuropathic pain have sodium channel blocking properties, 52 which may contribute to their analgesic activity.…”

Section: Rufinamide Reduces Neuropathic Pain In the Mousementioning

confidence: 99%

Rufinamide Attenuates Mechanical Allodynia in a Model of Neuropathic Pain in the Mouse and Stabilizes Voltage-gated Sodium Channel Inactivated State

et al. 2013

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Background: Voltage-gated sodium channels dysregulation is important for hyperexcitability leading to pain persistence. Sodium channel blockers currently used to treat neuropathic pain are poorly tolerated. Getting new molecules to clinical use is laborious. We here propose a drug already marketed as anticonvulsant, rufinamide. Methods: We compared the behavioral effect of rufinamide to amitriptyline using the Spared Nerve Injury neuropathic pain model in mice. We compared the effect of rufinamide on sodium currents using in vitro patch clamp in cells expressing the voltage-gated sodium channel Nav1.7 isoform and on dissociated dorsal root ganglion neurons to amitriptyline and mexiletine. Results: In naive mice, amitriptyline (20 mg/kg) increased withdrawal threshold to mechanical stimulation from 1.3 (0.6-1.9) (median [95% CI]) to 2.3 g (2.2-2.5) and latency of withdrawal to heat stimulation from 13.1 (10.4-15.5) to 30.0 s (21.8-31.9), whereas rufinamide had no effect. Rufinamide and amitriptyline alleviated injury-induced mechanical allodynia for 4 h (maximal effect: 0.10 ± 0.03 g (mean ± SD) to 1.99 ± 0.26 g for rufinamide and 0.25 ± 0.22 g to 1.92 ± 0.85 g for amitriptyline). All drugs reduced peak current and stabilized the inactivated state of voltage-gated sodium channel Nav1.7, with similar effects in dorsal root ganglion neurons. Conclusions: At doses alleviating neuropathic pain, amitriptyline showed alteration of behavioral response possibly related to either alteration of basal pain sensitivity or sedative effect or both. Side-effects and drug tolerance/compliance are major problems with drugs such as amitriptyline. Rufinamide seems to have a better tolerability profile and could be a new alternative to explore for the treatment of neuropathic pain. P AIN is essential for survival as it serves as an alert to engage protective behavior. Neuropathic pain, caused by a lesion or disease of the somatosensory nervous system, affects 7% of the population 1 and possesses no protective purpose. Sodium channels are major targets for the development of new drug to treat neuropathic pain.2 Nerve injury changes the expression of sodium channels 3 which affects peripheral nerve hyperexcitability and ectopic discharges along the nerve, in the dorsal root ganglion or at the injury site.4,5 They are composed of a α-pore forming subunit associated to one or two β-modulating subunits. Nine genes encode for the α-subunits, Nav1.1-1.9. Current therapy for neuropathic pain involves adjuvant medications-not primarily developed for this purposesuch as anticonvulsants, antidepressants, or local anesthetics. Address correspondence to Dr. Suter: Pain Center, Department of Anesthesiology, CHUV, Avenue du Bugnon 46, 1011 Lausanne, Switzerland. marc.suter@chuv.ch. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. ANESTHESIOLOGY's articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.

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“…In addition, an antinociceptive effect induced by nortriptyline has been reported in chemical (formalin and acetic acid tests) or thermal assays (hot plate and tail flick tests). The results show a stronger antinociceptive effect in chemical tests than in thermal tests [18]. …”

Section: Discussionmentioning

confidence: 99%

Antinociceptive Synergism of Gabapentin and Nortriptyline in Mice with Partial Sciatic Nerve Ligation

Miranda¹,

Noriega²,

Zepeda

et al. 2015

Pharmacology

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Background and Methods: Neuropathic pain results from nerve injury, and gabapentin, an antiepileptic drug, has been approved for the treatment of several types of neuropathic pain. On the other hand, nortriptyline, an antidepressant drug, has been suggested as an alternative treatment. In partial sciatic nerve ligation (PSNL) mice, the interaction of gabapentin with nortriptyline was evaluated by the hot plate assay using isobolographic analysis. Results: Gabapentin (3-100 mg/kg, i.p.) or nortriptyline (1-30 mg/kg, i.p.) induced dose-dependent antinociception, with an ED₅₀ of 11.60 ± 0.54 mg/kg for gabapentin and of 5.16 ± 0.21 mg/kg for nortriptyline. The potency of gabapentin and nortriptyline in PSNL mice at 7 and 14 days after ligation was significantly increased (p < 0.05). Coadministration of gabapentin with nortriptyline, at a 1:1 ratio of their ED₅₀, had a synergistic effect, with an interaction index of 0.311 and 0.348 for these mice at 7 and 14 days, respectively. Conclusion: The data showed a synergy in antinociception at a gabapentin-to-nortriptyline ratio of 1:1 in PSNL mice. This finding suggests that this combination could provide a therapeutic alternative that can be used for neuropathic pain management.

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Antinociceptive effects of tricyclic antidepressants and their noradrenergic metabolites

Cited by 31 publications

References 49 publications

Usefulness of Antidepressants for Improving the Neuropathic Pain-Like State and Pain-Induced Anxiety through Actions at Different Brain Sites

Usefulness of Antidepressants for Improving the Neuropathic Pain-Like State and Pain-Induced Anxiety through Actions at Different Brain Sites

Rufinamide Attenuates Mechanical Allodynia in a Model of Neuropathic Pain in the Mouse and Stabilizes Voltage-gated Sodium Channel Inactivated State

Antinociceptive Synergism of Gabapentin and Nortriptyline in Mice with Partial Sciatic Nerve Ligation

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