The Antiallodynic Effect of Neurotropin® Is Mediated via Activation of Descending Pain Inhibitory Systems in Rats with Spinal Nerve Ligation

Okazaki, Ryohei; Namba, Hiroyoshi; Yoshida, Hiroyuki; Okai, Hisashi; Miura, Tomoshi; Kawamura, Minoru

doi:10.1213/ane.0b013e31817e7a59

Cited by 53 publications

(29 citation statements)

References 29 publications

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“…Consistent with these views and a recent study (Dogrul et al, 2009), our data showed that blockade of spinal 5-HT 3 receptor function by intrathecal Y25130, a selective 5-HT 3 receptor antagonist, attenuated mechanical and thermal hypersensitivity following L5 SNL in rats. Interestingly, recent studies reported that intrathecal injection of 5-HT 3 receptor antagonists such as CGP35348 (Okazaki et al, 2008) or ondansetron (Peters et al, 2010) had no preventive effects on mechanical allodynia and/or thermal hyperalgesia in a rat with L5/6 SNL, which conflicts with the study with the same drug ondansetron in the same SNL model (Dogrul et al, 2009) and our results. However, we noticed that there were no expected plastic changes of both 5-HT immunoreactive intensity and 5-HT 3 receptor innervation in the lumbar spinal dorsal horn at 14 d after L5/L6 SNL in the study reported by Peters and colleagues (Peters et al, 2010).…”

Section: Discussioncontrasting

confidence: 99%

Spinal 5-HT₃Receptor Activation Induces Behavioral Hypersensitivity via a Neuronal-Glial-Neuronal Signaling Cascade

Miyoshi

Dubner

et al. 2011

J. Neurosci.

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Recent studies indicate that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in brainstem and the 5-HT3 receptor subtype in the spinal dorsal horn are involved in enhanced descending pain facilitation after tissue and nerve injury. However, the mechanisms underlying the activation of the 5-HT3 receptor and its contribution to facilitation of pain remain unclear. In the present study, activation of spinal 5-HT3 receptor by intrathecal injection of a selective 5-HT3 receptor agonist SR 57227 induced spinal glial hyperactivity, neuronal hyperexcitability and pain hypersensitivity in rats. We found that there was neuron-to-microglia signaling via chemokine fractalkine, microglia to astrocyte signaling via cytokine IL-18, astrocyte to neuronal signaling by IL-1β, and enhanced activation of GluN (NMDA) receptors in the spinal dorsal horn. In addition, exogenous BDNF-induced descending pain facilitation was accompanied with up-regulation of CD11b and GFAP expression in the spinal dorsal horn after microinjection in the RVM, which were significantly prevented by functional blockade of spinal 5-HT3 receptors. Enhanced expression of spinal CD11b and GFAP after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference. Thus, these findings offer new insights into the cellular and molecular mechanisms at the spinal level responsible for descending 5-HT-mediated pain facilitation during the development of persistent pain after tissue and nerve injury. New pain therapies should focus on prime targets of descending facilitation-induced glial involvement, and in particular the blocking of intercellular signaling transduction between neuron and glia.

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Section: Discussioncontrasting

confidence: 99%

Spinal 5-HT₃Receptor Activation Induces Behavioral Hypersensitivity via a Neuronal-Glial-Neuronal Signaling Cascade

Miyoshi

Dubner

et al. 2011

J. Neurosci.

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“…Consistent with these views and a recent study [50], our data showed that blockade of spinal 5-HT 3 receptor function by intrathecal Y25130, a selective 5-HT 3 receptor antagonist, attenuated mechanical and thermal hypersensitivity following L5 SNL in rats. Interestingly, some studies reported that intrathecal injection of 5-HT 3 receptor antagonists such as CGP35348 [51] or ondansetron [52] had no preventive effects on mechanical allodynia and/or thermal hyperalgesia in a rat with L5/6 SNL, which conflicts with the study with the same drug ondansetron in the same SNL model [50] and our results. However, we noticed that there were no expected plastic changes of both 5-HT immunoreactive intensity and 5-HT 3 receptor innervation in the lumbar spinal dorsal horn at 14 d after L5/L6 SNL in the study reported by Peters and colleagues [52].…”

Section: Discussioncontrasting

confidence: 99%

Spinal 5-HT₃ Receptors Mediate Descending Facilitation and Contribute to Behavioral Hypersensitivity via a Reciprocal Neuron-Glial Signaling Cascade

et al. 2014

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BackgroundIt has been recently recognized that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in the brainstem and the 5-HT3 receptor subtype in the spinal dorsal horn are involved in enhanced descending pain facilitation after tissue and nerve injury. However, the mechanisms underlying the activation of the 5-HT3 receptor and its contribution to facilitation of pain remain unclear.ResultsIn the present study, activation of spinal 5-HT3 receptors by intrathecal injection of a selective 5-HT3 receptor agonist SR 57227 induced spinal glial hyperactivity, neuronal hyperexcitability and pain hypersensitivity in rats. We found that there was neuron-to-microglia signaling via the chemokine fractalkine, microglia to astrocyte signaling via cytokine IL-18, astrocyte to neuronal signaling by IL-1β, and enhanced activation of NMDA receptors in the spinal dorsal horn. Glial hyperactivation in spinal dorsal horn after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference.ConclusionsThese findings offer new insights into the cellular and molecular mechanisms at the spinal level responsible for descending 5-HT-mediated pain facilitation during the development of persistent pain after tissue and nerve injury. New pain therapies should focus on prime targets of descending facilitation-induced glial involvement, and in particular the blocking of intercellular signaling transduction between neurons and glia.

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“…Neurotropin is an extract from the inflamed skin of vaccinia virus-inoculated rabbits which has been postulated to act by enhancing descending pain inhibitory systems involving 5-HT3 and noradrenergic alpha2 receptors in spinal dorsal www.futuremedicine.com horn [91,92] and in the locus ceruleus [93]. This compound has been used in Japan for many years to treat various chronic painful conditions, including fibromyalgia.…”

Section: Neurotropinmentioning

confidence: 99%

Fibromyalgia Syndrome: Novel Therapeutic Targets

Ablin

Haüser

2016

Pain Manag.

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Fibromyalgia syndrome (FMS) is a chronic disorder characterized by widespread pain and tenderness, accompanied by disturbed sleep, chronic fatigue and multiple additional functional symptoms. FMS continues to pose an unmet need regarding pharmacological treatment and many patients fail to achieve sufficient relief from existing treatments. As FMS is considered to be a condition in which pain amplification occurs within the CNS, therapeutic interventions, both pharmacological and otherwise, have revolved around attempts to influence pain processing in the CNS. In the current review, we present an update on novel targets in the search for effective treatment of FMS.

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The Antiallodynic Effect of Neurotropin® Is Mediated via Activation of Descending Pain Inhibitory Systems in Rats with Spinal Nerve Ligation

Cited by 53 publications

References 29 publications

Spinal 5-HT₃Receptor Activation Induces Behavioral Hypersensitivity via a Neuronal-Glial-Neuronal Signaling Cascade

Spinal 5-HT₃Receptor Activation Induces Behavioral Hypersensitivity via a Neuronal-Glial-Neuronal Signaling Cascade

Spinal 5-HT₃ Receptors Mediate Descending Facilitation and Contribute to Behavioral Hypersensitivity via a Reciprocal Neuron-Glial Signaling Cascade

Fibromyalgia Syndrome: Novel Therapeutic Targets

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The Antiallodynic Effect of Neurotropin® Is Mediated via Activation of Descending Pain Inhibitory Systems in Rats with Spinal Nerve Ligation

Cited by 53 publications

References 29 publications

Spinal 5-HT3Receptor Activation Induces Behavioral Hypersensitivity via a Neuronal-Glial-Neuronal Signaling Cascade

Spinal 5-HT3Receptor Activation Induces Behavioral Hypersensitivity via a Neuronal-Glial-Neuronal Signaling Cascade

Spinal 5-HT3 Receptors Mediate Descending Facilitation and Contribute to Behavioral Hypersensitivity via a Reciprocal Neuron-Glial Signaling Cascade

Fibromyalgia Syndrome: Novel Therapeutic Targets

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Product

Resources

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Spinal 5-HT₃Receptor Activation Induces Behavioral Hypersensitivity via a Neuronal-Glial-Neuronal Signaling Cascade

Spinal 5-HT₃Receptor Activation Induces Behavioral Hypersensitivity via a Neuronal-Glial-Neuronal Signaling Cascade

Spinal 5-HT₃ Receptors Mediate Descending Facilitation and Contribute to Behavioral Hypersensitivity via a Reciprocal Neuron-Glial Signaling Cascade