Cyclotraxin-B, a New TrkB Antagonist, and Glial Blockade by Propentofylline, Equally Prevent and Reverse Cold Allodynia Induced by BDNF or Partial Infraorbital Nerve Constriction in Mice

Constandil, Luís; Goich, Mariela; Hernández, Alejandro; Bourgeais, Laurence; Cazorla, Maxime; Hamon, Michel; Villanueva, Luis

doi:10.1016/j.jpain.2012.03.008

Cited by 31 publications

(25 citation statements)

References 54 publications

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“…As detailed in Table 1, the antidepressant amitriptyline, alone or combined with gabapentin, the anti-migraine drug naratriptan, the 5-HT 1A/7 receptor agonist 8-OH-DPAT, the 5-HT 3 receptor antagonist ondansetron, the BDNF-Trk B receptor blocker cyclotraxin B, at effective doses to reduce pain in validated neuropathic models in rodents [34]–[39], exerted no anti-allodynic effects up to 3 hours after acute administration in SCT rats.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, Constandil et al [34] reported that this drug can prevent and reverse neuropathic pain caused by peripheral nerve ligation in rats. In contrast, we found that cyclotraxin B was unable to reduce allodynia in SCT rats (Table 1), in line with RT-qPCR determinations which suggested that spinal BDNF expression would not be upregulated (in contrast to that observed in peripheral neuropathic pain models [66], [67]) but rather downregulated after thoracic cord transection, as previously reported after other types of SCI in rats [68], [69].…”

Section: Discussionmentioning

confidence: 99%

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Spinal Cord Transection-Induced Allodynia in Rats – Behavioral, Physiopathological and Pharmacological Characterization

et al. 2014

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In humans, spinal cord lesions induce not only major motor and neurovegetative deficits but also severe neuropathic pain which is mostly resistant to classical analgesics. Better treatments can be expected from precise characterization of underlying physiopathological mechanisms. This led us to thoroughly investigate (i) mechanical and thermal sensory alterations, (ii) responses to acute treatments with drugs having patent or potential anti-allodynic properties and (iii) the spinal/ganglion expression of transcripts encoding markers of neuronal injury, microglia and astrocyte activation in rats that underwent complete spinal cord transection (SCT). SCT was performed at thoracic T8–T9 level under deep isoflurane anaesthesia, and SCT rats were examined for up to two months post surgery. SCT induced a marked hyper-reflexia at hindpaws and strong mechanical and cold allodynia in a limited (6 cm2) cutaneous territory just rostral to the lesion site. At this level, pressure threshold value to trigger nocifensive reactions to locally applied von Frey filaments was 100-fold lower in SCT- versus sham-operated rats. A marked up-regulation of mRNAs encoding ATF3 (neuronal injury) and glial activation markers (OX-42, GFAP, P2×4, P2×7, TLR4) was observed in spinal cord and/or dorsal root ganglia at T6-T11 levels from day 2 up to day 60 post surgery. Transcripts encoding the proinflammatory cytokines IL-1β, IL-6 and TNF-α were also markedly but differentially up-regulated at T6–T11 levels in SCT rats. Acute treatment with ketamine (50 mg/kg i.p.), morphine (3–10 mg/kg s.c.) and tapentadol (10–20 mg/kg i.p.) significantly increased pressure threshold to trigger nocifensive reaction in the von Frey filaments test, whereas amitriptyline, pregabalin, gabapentin and clonazepam were ineffective. Because all SCT rats developed long lasting, reproducible and stable allodynia, which could be alleviated by drugs effective in humans, thoracic cord transection might be a reliable model for testing innovative therapies aimed at reducing spinal cord lesion-induced central neuropathic pain.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Spinal Cord Transection-Induced Allodynia in Rats – Behavioral, Physiopathological and Pharmacological Characterization

et al. 2014

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“…Importantly, knock out of the preprotachykinin A gene encoding for SP reduces mechanical allodynia that develops in MOR mice [71]. Brainderived neurotrophic factor (BDNF) is released during bursting activity [56], and can induce cold allodynia [24] and contribute to mechanical allodynia [64,94], two sensory abnormalities demonstrated in the MOR mice [12]. …”

Section: Discussionmentioning

confidence: 99%

Systemic morphine treatment induces changes in firing patterns and responses of nociceptive afferent fibers in mouse glabrous skin

Hogan¹,

Baker²,

Morón³

et al. 2013

Pain

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Patients receiving opioids for pain may experience decreased effectiveness of the drug and even abnormal pain sensitivity -either hyperalgesia and/or allodynia. We hypothesize that peripheral nociceptor hyperexcitability contributes to opioid-induced hyperalgesia and test this using an in vitro mouse glabrous skin-nerve preparation. Mice were injected i.p. with escalating doses of morphine (5, 8, 10, 15 mg/kg) or saline every 12 h for 48 h and sacrificed ~12 h following the last injection. Receptive fields of nociceptors were tested for mechanical, heat, and cold sensitivity. Activity was also measured during an initial 2 min period and during 5 min periods between stimuli. Aberrant activity was common in fibers from morphine-treated mice but rare in salinetreated mice. Resting background activity was elevated in C-fibers from morphinetreated mice. Both C-and A -fibers had afterdischarge in response to mechanical, heat and/or cold stimulation of the skin as well as spontaneous, unevoked activity. Compared to saline, morphine treatment increased the proportion of fibers displaying polymodal rather than mechanical-only responses. A significant increase in A -mechanoreceptive fibers responding to cold accounted for most of this change. In agreement with this, morphine-treated mice showed increased sensitivity in the cold tail flick test. In morphine-treated mice, aberrant activity and hyperexcitability of nociceptors could contribute to increased pain sensitivity. Importantly, this activity is likely driving central sensitization, a phenomenon contributing to abnormal sensory processing and chronic pain. If similar changes occur in human patients, aberrant nociceptor activity is likely to be interpreted as pain, and could contribute to opioid-induced hyperalgesia.

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“…For instance, PPF has been shown to reinstate the decreased expression of glutamate transporters GLT-1 and GLAST produced for the L5 nerve transection in mice [38], thus promoting glial glutamate uptake and thereby glutamate excitotoxicity, therefore decreasing nociception by a mechanism different from proinflammatory cytokine repression. Furthermore, it has been reported that PPF decreases hyperalgesia induced by intracisternal BDNF administration [39], which may constitute another different mechanism from the previously mentioned. BDNF synthesis is increased not only in primary afferents during chronic pain [40,41] but also in second-order nociceptive neurons [42,43] and glial cells [44,45] of the dorsal horn.…”

Section: Discussionmentioning

confidence: 99%

Antinociceptive interaction of (±)-CPP and propentofylline in monoarthritic rats

et al. 2012

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IntroductionMultiple studies have shown that glial cells of the spinal cord, such as astrocytes and microglia, have close contact with neurons, suggesting the term tripartite synapse. In these synapses, astrocytes surrounding neurons contribute to neuronal excitability and synaptic transmission, thereby increasing nociception and thus the persistence of chronic pain. Conversely, the N-methyl-D-aspartate (NMDA) receptor is crucial in the generation and maintenance of chronic pain. It has multiple sites of modulation. One is the site of recognition of extracellular neurotransmitter (glutamate), which can be blocked by competitive antagonists such as (3-(2-carboxipiperazin-4)1-propyl phosphonic acid), (±)-CPP, resulting in a blockade of the calcium current and thus the intracellular transduction process. In the present study, we investigated whether the potential antinociceptive effect of glial inhibition produced by propentofylline (PPF) can be enhanced when combined with an NMDA-receptor inhibitor such as (±)-CPP.MethodsWe used Sprague-Dawley monoarthritic rats. The monoarthritis was induced by injection of complete Freund adjuvant in the right tibiotarsal joint. Four weeks later, rats were treated with PPF (1, 10, 30, and 100 μg/10 μl) intrathecally (i.t.) for 10 days, injected once with (±)-CPP (2.5, 5, 12.5, 25, 50, and 100 μg/10 μl, i.t.), or both treatments combined. The antinociceptive effect was evaluated on day 11 for PPF and immediately to (±)-CPP, by assessing the vocalization threshold to mechanical stimulation of the arthritic paw.ResultsThe data indicate that intrathecal administration of increasing concentrations of (±)-CPP or PPF produced a significant dose-dependent antinociceptive effect with respect to monoarthritic rats receiving saline. The linear regression analysis showed that the dose that produces 30% of maximal effect (ED30) for i.t. (±)-CPP was 3.97 μg, and 1.42 μg for i.t. PPF. The administration of the PPF and (±)-CPP combination in fixed proportions of ED30 produced a dose-dependent antinociceptive effect, showing an interaction of the supraadditive type.ConclusionsThe results suggest that glia inhibitors can synergically potentiate the effect of glutamate blockers for the treatment of chronic inflammatory pain.

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Cyclotraxin-B, a New TrkB Antagonist, and Glial Blockade by Propentofylline, Equally Prevent and Reverse Cold Allodynia Induced by BDNF or Partial Infraorbital Nerve Constriction in Mice

Cited by 31 publications

References 54 publications

Spinal Cord Transection-Induced Allodynia in Rats – Behavioral, Physiopathological and Pharmacological Characterization

Spinal Cord Transection-Induced Allodynia in Rats – Behavioral, Physiopathological and Pharmacological Characterization

Systemic morphine treatment induces changes in firing patterns and responses of nociceptive afferent fibers in mouse glabrous skin

Antinociceptive interaction of (±)-CPP and propentofylline in monoarthritic rats

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