Long-term administration of fluvoxamine attenuates neuropathic pain and involvement of spinal serotonin receptors in diabetic model rats. Kato Takahiro,Kajiyama Seiji,Hamada Hiroshi,Kawamoto Masashi Hiroshima journal of medical sciences Diabetic neuropathic pain management is difficult even with non-steroidal anti-inflammatory drugs and narcotic analgesics such as morphine. Fluvoxamine, a class of selective serotonin reuptake inhibitors (SSRIs), is widely used to treat depression. Its analgesic effects are also documented for diabetic neuropathic pain, but they are limited because it is administered as a single-dose. In this study, we examined the time course of the antiallodynic effect of fluvoxamine in a rat model of diabetic neuropathic pain, which was induced by a single intraperitoneal administration of streptozotocin (75 mg/kg). In addition, the involvement of spinal serotonin (5-HT) receptors in long-term fluvoxamine treatment was studied by intrathecal administration of 5-HT receptor antagonists. In this study the development of mechanical hyperalgesia was assessed by measuring the hind paw withdrawal threshold using von Frey filaments. The results demonstrated that daily oral administration of fluvoxamine (10, 30, and 100 mg/kg) to diabetic rats from 3 to 8 weeks after streptozotocin administration resulted in a dose-dependent antiallodynic effect. The antiallodynic effect was sustained from 2 to 5 weeks after fluvoxamine administration. The antiallodynic effect of fluvoxamine in the diabetic rats was attenuated by WAY-100635 (a 5-HT(1A) receptor antagonist) intrathecally administered 1 week after the onset of daily administration of fluvoxamine, whereas no significant attenuation was seen when the antagonist was administered 3 and 5 weeks after fluvoxamine administration. The antiallodynic effect of fluvoxamine was also attenuated by ketanserin (a 5-HT(2A/2C) receptor antagonist) and ondansetron (a 5-HT3 receptor antagonist) intrathecally administered 1 and 3 weeks after the onset of daily fluvoxamine administration. However, no significant attenuation was observed when the antagonist was administered 5 weeks after fluvoxamine administration. This study demonstrated that daily oral administration of fluvoxamine can afford a sustained antiallodynic effect against streptozotocin-induced neuropathic pain. Furthermore, there appears to be a time-dependent relevance of different types of 5-HT receptors (5-HT(1A), 5-HT(2A/2C), and 5-HT3) to streptozotocin-induced diabetic neuropathic pain when treated with daily fluvoxamine.

The TRPM8 channel forms a complex with the 5-HT(1B) receptor and phospholipase D that amplifies its reversal of pain hypersensitivity. Vinuela-Fernandez Ignacio,Sun Liting,Jerina Helen,Curtis John,Allchorne Andrew,Gooding Hayley,Rosie Roberta,Holland Pamela,Tas Basak,Mitchell Rory,Fleetwood-Walker Sue Neuropharmacology Effective relief from chronic hypersensitive pain states remains an unmet need. Here we report the discovery that the TRPM8 ion channel, co-operating with the 5-HT(1B) receptor (5-HT(1B)R) in a subset of sensory afferents, exerts an influence at the spinal cord level to suppress central hypersensitivity in pain processing throughout the central nervous system. Using cell line models, ex vivo rat neural tissue and in vivo pain models, we assessed functional Ca(2+) fluorometric responses, protein:protein interactions, immuno-localisation and reflex pain behaviours, with pharmacological and molecular interventions. We report 5-HT(1B)R expression in many TRPM8-containing afferents and direct interaction of these proteins in a novel multi-protein signalling complex, which includes phospholipase D1 (PLD1). We provide evidence that the 5-HT(1B)R activates PLD1 to subsequently activate PIP 5-kinase and generate PIP2, an allosteric enhancer of TRPM8, achieving a several-fold increase in potency of TRPM8 activation. The enhanced activation responses of synaptoneurosomes prepared from spinal cord and cortical regions of animals with a chronic inflammatory pain state are inhibited by TRPM8 activators that were applied in vivo topically to the skin, an effect potentiated by co-administered 5-HT(1B)R agonists and attenuated by 5-HT(1B)R antagonists, while 5-HT(1B)R agents alone had no detectable effect. Corresponding results are seen when assessing reflex behaviours in inflammatory and neuropathic pain models. Control experiments with alternative receptor/TRP channel combinations reveal no such synergy. Identification of this novel receptor/effector/channel complex and its impact on nociceptive processing give new insights into possible strategies for enhanced analgesia in chronic pain. 10.1016/j.neuropharm.2013.11.006

The Analgesic Effect of Venlafaxine and Its Mechanism on Oxaliplatin-Induced Neuropathic Pain in Mice. Li Daxian,Lee Ji Hwan,Choi Chang Won,Kim Jaihwan,Kim Sun Kwang,Kim Woojin International journal of molecular sciences The analgesic effect of venlafaxine (VLX), which is a selective serotonin and noradrenaline reuptake inhibitor (SNRI), has been observed on oxaliplatin-induced neuropathic pain in mice. Significant allodynia was shown after oxaliplatin treatment (6 mg/kg, i.p.); acetone and von Frey hair tests were used to assess cold and mechanical allodynia, respectively. Intraperitoneal administration of VLX at 40 and 60 mg/kg, but not 10 mg/kg, significantly alleviated these allodynia. Noradrenaline depletion by pretreatment of -(2-Chloroethyl)--ethyl-2-bromobenzylamine (DSP-4, 50 mg/kg, i.p.) blocked the relieving effect of VLX (40 mg/kg, i.p.) on cold and mechanical allodynia. However, serotonin depletion by three consecutive pretreatments of para-chlorophenylalanine (PCPA, 150 mg/kg/day, i.p.) only blocked the effect of VLX on mechanical allodynia. In cold allodynia, the α₂-adrenergic antagonist idazoxan (10 μg, i.t.), but not the α₁-adrenergic antagonist prazosin (10 μg, i.t.), abolished VLX-induced analgesia. Furthermore, idazoxan and 5-HT₃ receptor antagonist bemesetron (MDL-72222, 15 μg, i.t.), but not prazosin or mixed 5-HT receptor antagonist methysergide (10 μg, i.t.), abolished VLX-induced analgesia in mechanical allodynia. In conclusion, 40 mg/kg of VLX treatment has a potent relieving effect against oxaliplatin-induced neuropathic pain, and α₂-adrenergic receptor, and both α₂-adrenergic and 5-HT₃ receptors are involved in this effect of VLX on cold and mechanical allodynia, respectively. 10.3390/ijms20071652

Role of spinal 5-HT5A, and 5-HT1A/1B/1D, receptors in neuropathic pain induced by spinal nerve ligation in rats. Avila-Rojas Sabino Hazael,Velázquez-Lagunas Isabel,Salinas-Abarca Ana Belen,Barragán-Iglesias Paulino,Pineda-Farias Jorge Baruch,Granados-Soto Vinicio Brain research Serotonin (5-HT) participates in pain modulation by interacting with different 5-HT receptors. The role of 5-HT5A receptor in neuropathic pain has not previously studied. The purpose of this study was to investigate: A) the role of 5-HT5A receptors in rats subjected to spinal nerve injury; B) the expression of 5-HT5A receptors in dorsal spinal cord and dorsal root ganglia (DRG). Neuropathic pain was induced by L5/L6 spinal nerve ligation. Tactile allodynia in neuropathic rats was assessed with von Frey filaments. Western blot methodology was used to determine 5-HT5A receptor protein expression. Intrathecal administration (on day 14th) of 5-HT (10-100 nmol) or 5-carboxamidotryptamine (5-CT, 0.03-0.3 nmol) reversed nerve injury-induced tactile allodynia. Intrathecal non-selective (methiothepin, 0.1-0.8 nmol) and selective (SB-699551, 1-10 nmol) 5-HT5A receptor antagonists reduced, by ~60% and ~25%, respectively, the antiallodynic effect of 5-HT (100 nmol) or 5-CT (0.3 nmol). Moreover, both selective 5-HT1A and 5-HT1B/1D receptor antagonists, WAY-100635 (0.3-1 nmol) and GR-127935 (0.3-1 nmol), respectively, partially diminished the antiallodynic effect of 5-HT or 5-CT by about 30%. Injection of antagonists, by themselves, did not affect allodynia. 5-HT5A receptors were expressed in the ipsilateral dorsal lumbar spinal cord and DRG and L5/L6 spinal nerve ligation did not modify 5-HT5A receptor protein expression in those sites. Results suggest that 5-HT5A receptors reduce pain processing in the spinal cord and that 5-HT and 5-CT reduce neuropathic pain through activation of 5-HT5A and 5-HT1A/1B/1D receptors. These receptors could be an important part of the descending pain inhibitory system. 10.1016/j.brainres.2015.06.043

Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT(1A) receptors without diminishing nervous system function or chemotherapy efficacy. Ward Sara Jane,McAllister Sean D,Kawamura Rumi,Murase Ryuchi,Neelakantan Harshini,Walker Ellen A British journal of pharmacology BACKGROUND AND PURPOSE:Paclitaxel (PAC) is associated with chemotherapy-induced neuropathic pain (CIPN) that can lead to the cessation of treatment in cancer patients even in the absence of alternate therapies. We previously reported that chronic administration of the non-psychoactive cannabinoid cannabidiol (CBD) prevents PAC-induced mechanical and thermal sensitivity in mice. Hence, we sought to determine receptor mechanisms by which CBD inhibits CIPN and whether CBD negatively effects nervous system function or chemotherapy efficacy. EXPERIMENTAL APPROACH:The ability of acute CBD pretreatment to prevent PAC-induced mechanical sensitivity was assessed, as was the effect of CBD on place conditioning and on an operant-conditioned learning and memory task. The potential interaction of CBD and PAC on breast cancer cell viability was determined using the MTT assay. KEY RESULTS:PAC-induced mechanical sensitivity was prevented by administration of CBD (2.5 - 10 mg·kg⁻¹) in female C57Bl/6 mice. This effect was reversed by co-administration of the 5-HT(1A) antagonist WAY 100635, but not the CB₁ antagonist SR141716 or the CB₂ antagonist SR144528. CBD produced no conditioned rewarding effects and did not affect conditioned learning and memory. Also, CBD + PAC combinations produce additive to synergistic inhibition of breast cancer cell viability. CONCLUSIONS AND IMPLICATIONS:Our data suggest that CBD is protective against PAC-induced neurotoxicity mediated in part by the 5-HT(1A) receptor system. Furthermore, CBD treatment was devoid of conditioned rewarding effects or cognitive impairment and did not attenuate PAC-induced inhibition of breast cancer cell viability. Hence, adjunct treatment with CBD during PAC chemotherapy may be safe and effective in the prevention or attenuation of CIPN. 10.1111/bph.12439