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INTRODUCTION: Apart from epilepsy treatment, anticonvulsant drugs are also extensively used as efficacious therapy of diverse non-epileptic conditions, including pain (neuropathic pain, migraine prophylaxis), neuromuscular disorders and psychiatric disorders (anxiety, bipolar affective disorder). Therefore, continued preclinical searching for new anticonvulsant drugs with collateral antinociceptive activity are expected since they lead to further advancements in the treatment of epilepsy, as well as neuropathic pain. AIM(S): The aim of the study was to examine analgesic activity of three new 3,3-diphenyl-propionamides, which demonstrated in the previous research anticonvulsant activity in the MES (the maximal electroshock seizure) and scPTZ (subcutaneous pentylenetetrazole) tests in mice. METHOD(S): The antinociceptive properties were estimated in four models of pain in mice – the hot plate test (acute pain), the formalin test (tonic pain), the oxaliplatin-induced neuropathy (neuropathic pain), and the streptozotocin-induced diabetic neuropathy. RESULTS: In the hot plate test the greatest effect possessed compound JOA 122, which at a dose of 30 mg/kg significantly prolonged the latency time to pain reaction. In the formalin test a significant antinociceptive activity was observed for compounds JOA 122 and JOA 123 in the second (late) phase. In this phase the compound JOA 122 tested at the doses 1, 10, 30 mg/kg reduced duration of licking response. Compound JOA 123 attenuated the nocifensive response in this phase only at the dose 30 mg/kg. In the oxaliplatin-induced neuropathy, as well as streptozotocin-induced neuropathy tested compounds at the dose of 30 mg/kg attenuated tactile allodynia, since they significantly elevated the pain sensitivity threshold in the acute phase. CONCLUSIONS: The results obtained in the current studies proved that in the group of novel 3,3-diphenyl-propionamides new anticonvulsants with collateral analgesic properties can be found. FINANCIAL SUPPORT: Supported by the grant of the Polish National Scientific Centre, Poland (Grant No. DEC-2013/11/B/NZ7/02081).
Serotonin (5-HT) and its receptors play a multifaceted role in pain modulation. Among the many subtypes of 5-HT receptors potentially contributing to medullo-spinal modulation of pain, 5-HT1A and 5-HT7 receptors have significant role, as it is expressed both in supraspinal and spinal areas. A series of newly synthesized 3,3-disubstituted pyrrolidine-2,5-diones with affinity for 5-HT1A and 5-HT7 receptors was investigated in some behavioral tests in mice. Previous studies showed antiepileptic activity of these compounds in experimental models of seizures, i.e. induced by pentylentetrazole, maximal electroshock, and psychomotor ones (6-Hz). Many antiepileptic drugs (e.g. carbamazepine, valproinic acid) possess analgesic activity, especially in neuropathic pain treatment. Hence it was an intriguing question, if these new structures may be useful as an analgesics. An antinociceptive effect of four new 3,3-disubstituted pyrrolidine-2,5-diones (JOP364, JOP362, JOP346, and JOP315) was determined in model of acute pain: the hot-plate (phasic pain model) and their activity was compared with effects of the reference drugs tramadol and morphine. Measured antinocicepitve latency of two investigated compounds (JOP364 and JOP 362) in the hot plate test was comparable with tramadol, while the compound JOP315 was inactive in this test. The obtained results entitle to lead further examinations to establish mechanism(s) of analgesic activity of these new derivatives and to estimate their potential therapeutic value.
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