Article

Anti-nociception is selectively enhanced by parallel inhibition of multiple subtypes of monoamine transporters in rat models of persistent and neuropathic pain

Department of Pharmacology, NeuroSearch A/S, 93 Pederstrupvej, 2750, Ballerup, Denmark.
Psychopharmacology (Impact Factor: 3.88). 12/2005; 182(4):551-61. DOI: 10.1007/s00213-005-0120-6
Source: PubMed

ABSTRACT

Neuropathic pain is characterised by hyperexcitability within nociceptive pathways that manifests behaviourally as allodynia and hyperalgesia and remains difficult to treat with standard analgesics. However, antidepressants have shown reasonable preclinical and clinical anti-nociceptive efficacy against signs and symptoms of neuropathic pain.
To ascertain whether inhibition of serotonin (5-HT) and/or noradrenaline (NA) and/or dopamine (DA) re-uptake preferentially mediates superior anti-nociception in preclinical pain models.
The 5-HT re-uptake inhibitor fluoxetine (3-30 mg/kg), the NA re-uptake inhibitor reboxetine (3-30 mg/kg), the dual 5-HT and NA re-uptake inhibitor venlafaxine (3-100 mg/kg) and the dual DA and NA re-uptake inhibitor bupropion (3-30 mg/kg) were tested after intraperitoneal administration in rat models of acute, persistent and neuropathic pain.
Reboxetine and venlafaxine dose-dependently attenuated second-phase flinching in the formalin test; fluoxetine attenuated flinching only at the highest dose tested, whereas bupropion was ineffective. In the chronic constriction injury (CCI) and spinal nerve ligation models of neuropathic pain, hindpaw mechanical allodynia was significantly attenuated by fluoxetine and particularly by bupropion. Reboxetine and venlafaxine were completely ineffective. In contrast, reboxetine and venlafaxine reversed thermal hyperalgesia in CCI rats, whereas bupropion and fluoxetine were either minimally effective or ineffective. Fluoxetine, reboxetine and venlafaxine transiently increased the tail-flick latency in uninjured animals. Anti-nociceptive doses of drugs had no effect on motor function.
Combined re-uptake inhibition of 5-HT and NA appears to confer a greater degree of anti-nociception in animal models of experimental pain than single mechanism of action inhibitors. The selective attenuation of mechanical allodynia by bupropion suggests that the additional re-uptake of DA may further augment 5-HT/NA re-uptake mediated anti-nociception after nerve injury.

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    • "These compounds block 5-HT, NE and DA transporters thereby increasing all three monoamine levels in the synapse (Guiard et al., 2009). Enhancement of dopaminergic neurotransmission might expand the favourable antidepressant (Bourin et al., 2009; Ghanbari et al., 2012) and analgesic (Pedersen et al., 2005) profile of SNRIs. In this regard, the TRI bicifadine attenuates nociceptive behaviours in animal models of acute, persistent and chronic pain (Basile et al., 2007). "

    Full-text · Article · Feb 2015 · European Journal of Pain
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    • "These compounds block 5-HT, NE and DA transporters thereby increasing all three monoamine levels in the synapse (Guiard et al., 2009). Enhancement of dopaminergic neurotransmission might expand the favourable antidepressant (Bourin et al., 2009; Ghanbari et al., 2012) and analgesic (Pedersen et al., 2005) profile of SNRIs. In this regard, the TRI bicifadine attenuates nociceptive behaviours in animal models of acute, persistent and chronic pain (Basile et al., 2007). "
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    ABSTRACT: Background Chronic neuropathic pain can lead to anxiety and depression. Drugs that block reuptake of serotonin, norepinephrine and/or dopamine are widely used to treat depression, and have emerged as useful drugs in the treatment of neuropathic pain. This study compared the acute antinociceptive effects of NS18283, a novel triple monoamine reuptake inhibitor (MRI) with indatraline, venlafaxine and escitalopram in a mouse model of neuropathic pain.Method Neuropathic pain-like behaviours were induced in mice by repeated injections of oxaliplatin (OXA), and assessed using the von Frey hair test, the cold plate test and the thermal preference plate test. Anxio/depressive phenotype and antidepressant-like properties of compounds were assessed by the novelty suppressed feeding test and the tail suspension test, respectively.ResultsIn vivo microdialysis experiments showed that each MRI increased extracellular serotonin, norepinephrine and/or dopamine levels in the cingulate cortex, in agreement with their in vitro reuptake inhibitory properties. Indatraline (3 mg/kg) reversed the full repertoire of OXA-induced neuropathic hypersensitivity. NS18283 (10 mg/kg) reversed OXA-induced mechano-hypersensitivity and cold allodynia. Venlafaxine (16 mg/kg) and escitalopram (4 mg/kg) only reversed cold allodynia and mechano-hypersensitivity, respectively. All MRIs produced antidepressant-like activity in anxio/depressive phenotype of OXA mice.Conclusions Acute administration of drugs that enhance the activity of serotonin, norepinephrine and dopamine neurotransmission within nociceptive pathways may provide a broader spectrum of antinociception than dual or selective reuptake inhibitors in animal models of neuropathic pain. Whether similar observations would occur after repeated administration of such compounds in an attempt to simulate dosing in humans, or be compromised by dopaminergic-mediated adverse effects warrants further investigation.
    Full-text · Article · Aug 2014 · European journal of pain (London, England)
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    • "In contrast to both tricyclic antidepressants, venlafaxine did not reverse thermal hyperalgesia, but attenuation of allodynia was observed at all of the time points with statistical significance measured only at the highest dose (25 mg). This result is inconsistent with the results obtained in 2005 by Pedersen et al. [43] in which venlafaxine was ineffective against mechanical allodynia in CCI and spinal nerve ligation models. This study also reported that venlafaxine transiently increased the tail-flick latency in uninjured animals and attenuated second-phase flinching in the formalin test in rats [43]. "
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    ABSTRACT: Background: The therapy of neuropathic pain may include the use of co-analgesics, such as antidepressants, however, their desired analgesic effect is associated with significant side effects. An alternative approach to this is their local administration which has been proposed, but there is little data regarding their local co-administration with morphine and the nature of the interaction between morphine and either doxepin or venlafaxine, two antidepressant drugs that have been recently used in neuropathic pain therapies. Methods: This study was performed on rats after chronic constriction injury (CCI) to the sciatic nerve. The von Frey and Hargreaves' tests were used to assess mechanical allodynia and thermal hyperalgesia, respectively, after intraplantar (ipl) or subcutaneous (sc) administration of amitriptyline, doxepin, or venlafaxine, or their ipl co-administration with morphine on day 12-16 after injury. Results: The ipl administration of amitriptyline (3, 15 mg), doxepin (1, 5, 10, 15 mg), or venlafaxine (2, 7 mg) was effective in antagonizing CCI-induced allodynia. Their sc injection at a site distal to the injured side, did not induce alterations in pain thresholds, which supports the local mode of action. Of the three antidepressants used in this study, only ipl co-administration of amitriptyline with morphine significantly enhanced its effect in contrast to doxepin and venlafaxine, both of which weakened the analgesic effect of morphine. Conclusions: In summary, the results suggest that when amitriptyline (but not doxepin or venlafaxine) is locally co-administered with morphine the effectiveness under neuropathic pain is enhanced, although additional studies are necessary to explain differential mechanisms of interaction of antidepressant drugs with morphine after local administration.
    Full-text · Article · Jun 2014 · Pharmacological reports: PR
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