Evaluation of the analgesic effects of ammoxetine, a novel potent serotonin and norepinephrine reuptake inhibitor

Abstract

Aim:The selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs) are commonly used for the treatment of neuropathic pain and fibromyalgia. Ammoxetine ((±)-3-(benzo [d] [1,3]dioxol-4-yloxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine) has been identified as a novel potent SNRI. In this study, we evaluated the acute analgesic properties of ammoxetine in different animal models of pain, and examined the involvement of monoamines in its analgesic actions. Methods: The analgesic effects of ammoxetine were assayed using models of acetic acid-and formalin-induced pain in mice, neuropathic pain induced by sciatic nerve injury (SNI), chronic constriction injury (CCI) and reserpine-induced fibromyalgia pain in rats. The contents of 5-HT and NE in brain regions of fibromyalgia rats were measured using HPLC-ECD. In all the experiments, duloxetine was used as a positive control drug. Results: Oral administration of ammoxetine (0.625-10 mg/kg) or duloxetine (2.5-40 mg/kg) dose-dependently decreased the number of acetic acid-induced writhing and formalin-induced first phase and second phase paw licking time in mice. Oral administration of ammoxetine (2.5-10 mg/kg) or duloxetine (10 mg/kg) alleviated mechanical allodynia in SNI and CCI rats and thermal hyperalgesia in CCI rats. The antiallodynic effect of ammoxetine in CCI rats was abolished by pretreatment with para-chlorophenylalanine methyl ester hydrochloride (PCPA, a 5-HT synthesis inhibitor) or α-methyl-para-tyrosine methylester (AMPT, a catecholamine synthesis inhibitor). Oral administration of ammoxetine (30 mg/kg) or duloxetine (50 mg/kg) significantly attenuated tactile allodynia in rats with reserpine-induced fibromyalgia. In the fibromyalgia rats, administration of ammoxetine (10, 30 mg/kg) or duloxetine (30, 50 mg/kg) dose-dependently increased the levels of 5-HT and NE, and decreased the metabolite ratio of 5-HT (5-HIAA/5-HT) in the spinal cord, hypothalamus, thalamus and prefrontal cortex. Conclusion: Ammoxetine effectively alleviates inflammatory, continuous, neuropathic and fibromyalgia-related pain in animal models, which can be attributed to enhanced neurotransmission of 5-HT and NE in the descending inhibitory systems.

Potential of animal models for advancing the understanding and treatment of pain in Parkinson’s disease

“…46,47 Reserpine treatment causes reduced mechanical and thermal nociceptive thresholds in rodents, 48,49 indicative of good face validity for pain in PD. The antinociceptive effects of duloxetine in this model, 50 further support an involvement of reduced serotonergic and noradrenergic signalling in the mechanical and thermal hypersensitivity. However, these pharmacological effects are not totally in line with clinical outcomes, casting some doubt on the predictive validity of this model.…”

Ammoxetine attenuates diabetic neuropathic pain through inhibiting microglial activation and neuroinflammation in the spinal cord

“…Our published data have proved that ammoxetine is a potent and balanced SNRI with superior antidepressant activity and lower cytotoxicity in HepG2 cells compared to duloxetine [ 24 – 26 ]. Ammoxetine displays acute efficacy in reversing mechanical allodynia in models of neuropathic pain, fibromyalgia-related pain, and inflammatory pain [ 27 ]. In this study, we evaluated the efficacy of a chronic ammoxetine treatment in DNP in STZ-induced diabetic rats.…”

Rescue of Noradrenergic System as a Novel Pharmacological Strategy in the Treatment of Chronic Pain: Focus on Microglia Activation

“…Noradrenaline is known to exert strong anti-inflammatory activity in the CNS (Mcnamee et al, 2010) and its endogenous neuroprotective role in chronic pain is likely linked to this action (Zhang et al, 2016b).…”

“…β-Adrenergic receptors are also abundantly expressed in glial cells of the rat spinal dorsal horn (Mizukami, 2004; Nicholson et al, 2005), where their activation was shown to control nociceptive transduction by attenuating microglial reactivity (Morioka et al, 2009; Zhang et al, 2016b). Systematic treatment with β-adrenergic receptor agonists resulted in antinociceptive effects in animal models of neuropathic pain (Choucair-Jaafar et al, 2009).…”

“…Systematic treatment with β-adrenergic receptor agonists resulted in antinociceptive effects in animal models of neuropathic pain (Choucair-Jaafar et al, 2009). Stimulation of spinal dorsal horn β2-adrenergic receptors in mice was also shown to ameliorate neuropathic mechanical hypersensitivity, following a partial sciatic nerve ligation, through reduction of phosphorylation of microglial p38 MAPK and astrocytic JNK (Zhang et al, 2016b). Evidence obtained in animal models is supported by in vitro studies in cultured rat spinal microglia where noradrenaline, via β-adrenergic receptors, downregulates inflammatory signaling including ATP-induced cAMP–protein kinase A–dependent phosphorylation of p38 MAPK and synthesis of TNF-α (Morioka et al, 2009).…”