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Effects of milnacipran, a 5‐HT and noradrenaline reuptake inhibitor, on C‐fibre‐evoked field potentials in spinal long‐term potentiation and neuropathic pain
Author(s) -
Ohnami S,
Kato A,
Ogawa K,
Shinohara S,
Ono H,
Tanabe M
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02007.x
Subject(s) - milnacipran , neuropathic pain , long term potentiation , nociception , idazoxan , neuroscience , spinal cord , anesthesia , neurotransmission , sciatic nerve , medicine , pharmacology , chemistry , psychology , serotonin , antagonist , receptor , prazosin
BACKGROUND AND PURPOSE The analgesic action of 5‐HT and noradrenaline reuptake inhibitors (SNRIs) on nociceptive synaptic transmission in the spinal cord is poorly understood. We investigated the effects of milnacipran, an SNRI, on C‐fibre‐evoked field potentials (FPs) in spinal long‐term potentiation (LTP), a proposed synaptic mechanism of hypersensitivity, and on the FPs in a neuropathic pain model. EXPERIMENTAL APPROACH C‐fibre‐evoked FPs by electrical stimulation of the sciatic nerve fibres were recorded in the spinal dorsal horn of anaesthetized adult rats, and LTP was induced by high‐frequency stimulation of the sciatic nerve fibres. A rat model of neuropathic pain was produced by L5 spinal nerve ligation and transection. KEY RESULTS Milnacipran produced prolonged inhibition of C‐fibre‐evoked FPs when applied spinally after the establishment of LTP of C‐fibre‐evoked FPs in naïve animals. In the neuropathic pain model, spinal administration of milnacipran clearly reduced the basal C‐fibre‐evoked FPs. These inhibitory effects of milnacipran were blocked by spinal administration of methysergide, a 5‐HT 1/2 receptor antagonist, and yohimbine or idazoxan, α 2 ‐adrenoceptor antagonists. However, spinal administration of milnacipran in naïve animals did not affect the basal C‐fibre‐evoked FPs and the induction of spinal LTP. CONCLUSION AND IMPLICATIONS Milnacipran inhibited C‐fibre‐mediated nociceptive synaptic transmission in the spinal dorsal horn after the establishment of spinal LTP and in the neuropathic pain model, by activating both spinal 5‐hydroxytryptaminergic and noradrenergic systems. The condition‐dependent inhibition of the C‐fibre‐mediated transmission by milnacipran could provide novel evidence regarding the analgesic mechanisms of SNRIs in chronic pain.