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ABSTRACT: Fibromyalgia is a prevalent musculoskeletal disorder characterized by chronic widespread pain that significantly reduces quality of life in patients. Due to the lack of consistently effective treatment, the development of improved therapies for treating fibromyalgia is necessary. As dysfunction of serotonergic analgesic control appears to be involved in the pathophysiology of fibromyalgia, the present study explored the potential of 5-HT2C receptor agonists as novel therapies for treating this disease. Three 5-HT2C receptor agonists (lorcaserin, vabicaserin and YM348) that have been suggested to be useful in the treatment of several central nervous system diseases, including obesity and schizophrenia, were used. The effect of systemic administration of these agents on the muscular hyperalgesia that develops in the reserpine-induced myalgia (RIM) rat, a putative animal model of fibromyalgia, was investigated. RIM rats exhibited decreased muscle pressure thresholds. Microdialysis experiments showed that the concentration of serotonin (5-HT) in the spinal cord of RIM rats was significantly lower than that of controls. Lorcaserin (0.3-3mg/kg p.o.), vabicaserin (0.3-3mg/kgs.c.) and YM348 (0.03-0.3mg/kg p.o.) recovered the muscle pressure threshold. The effect of lorcaserin was reversed by the pretreatment with SB242084, a 5-HT2C receptor antagonist. Our findings demonstrate that 5-HT2C receptors play a critical role in muscular hyperalgesia in RIM rats and suggest that 5-HT2C receptor agonists have therapeutic potential for treating chronic pain in patients with fibromyalgia although clinical extrapolation remains to be a future challenge.
Pharmacology Biochemistry and Behavior 04/2013; · 2.53 Impact Factor
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ABSTRACT: Transient receptor potential vanilloid 1 (TRPV1) is activated by a variety of stimulations, such as endogenous ligands and low pH, and is believed to play a role in pain transmission. TRPV1 antagonists have been reported to be effective in several animal pain models; however, some compounds induce hyperthermia in animals and humans. We discovered the novel TRPV1 antagonist (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide (AS1928370) in our laboratory. AS1928370 bound to the resiniferatoxin-binding site on TRPV1 and inhibited capsaicin-mediated inward currents with an IC₅₀ value of 32.5 nM. Although AS1928370 inhibited the capsaicin-induced Ca²(+) flux in human and rat TRPV1-expressing cells, the inhibitory effect on proton-induced Ca²(+) flux was extremely small. In addition, AS1928370 showed no inhibitory effects on transient receptor potential vanilloid 4, transient receptor potential ankyrin 1, and transient receptor potential melastatin 8 in concentrations up to 10 μM. AS1928370 improved capsaicin-induced secondary hyperalgesia and mechanical allodynia in an L5/L6 spinal nerve ligation model in rats with respective ED₅₀ values of 0.17 and 0.26 mg/kg p.o. Furthermore, AS1928370 alleviated inflammatory pain in a complete Freund's adjuvant model at 10 mg/kg p.o. AS1928370 had no effect on rectal body temperature up to 10 mg/kg p.o., although a significant hypothermic effect was noted at 30 mg/kg p.o. In addition, AS1928370 showed no significant effect on motor coordination. These results suggest that blockage of the TRPV1 receptor without affecting the proton-mediated TRPV1 activation is a promising approach to treating neuropathic pain because of the potential wide safety margin against hyperthermic effects. As such, compounds such as ASP1928370 may have potential as new analgesic agents for treating neuropathic pain.
Journal of Pharmacology and Experimental Therapeutics 03/2011; 336(3):743-50. · 3.83 Impact Factor
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ABSTRACT: Transient receptor potential vanilloid 1 (TRPV1) is primarily expressed in central and peripheral terminals of non-myelinated primary afferent neurons. We previously showed that AS1928370, a novel TRPV1 antagonist that can prevent ligand-induced activation but not proton-induced activation, ameliorates neuropathic pain in rats without hyperthermic effect. In this study, we investigated its analgesic profile in mice. AS1928370 showed good oral bioavailability and high penetration into the brain and spinal cord in mice. The mean plasma-to-brain and plasma-to-spinal cord ratios were 4.3 and 3.5, respectively. Pretreatment with AS1928370 significantly suppressed both capsaicin-induced acute pain and withdrawal response in hot plate test at 10-30 mg/kg per os (p.o.). At lower oral doses (0.3-1.0 mg/kg), AS1928370 improved mechanical allodynia in mice undergoing spinal nerve ligation. Intrathecal administration of AS1928370 (30 µg/body) also significantly suppressed mechanical allodynia. In addition, AS1928370 showed no effect on locomotor activity up to 30 mg/kg p.o. These results suggest that spinal TRPV1 has an important role in the transmission of neuropathic pain and that the central nervous system (CNS) penetrant TRPV1 receptor antagonist AS1928370 is a promising candidate for treating neuropathic pain.
Biological & Pharmaceutical Bulletin 01/2011; 34(7):1105-8. · 1.66 Impact Factor
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ABSTRACT: The paradigm of sine-wave electrical stimuli has been used for sensory neurological assessment in humans. In the present study, we applied the paradigm to the dog for the quantitative assessment of sensory function. Sine-wave electrical current stimuli at frequencies of 2000, 250, and 5Hz were delivered to bipolar electrodes attached to the skin surface of the hind paws. The stimulation intensity was gradually increased, and the minimum intensity required to elicit the lifting behavior in the stimulated paw was determined as current threshold (CT) for each of the three frequencies. Dogs consistently showed the lifting behavior at CTs without showing aversive behaviors such as vocalization and wriggling. The baseline CTs (mean+/-SEM, n=12) were 4430+/-110microA for CT2000, 2215+/-173microA for CT250, and 2305+/-152microA for CT5. The CTs immediately increased after bolus intravenous injection of fentanyl at 10microg/kg, although the significant increase disappeared within 1h. The time course for the CTs was parallel to that of plasma fentanyl concentration. In conclusion, the present study applied the paradigm of transcutaneous sine-wave electrical stimuli to the dog, and used the hind paw lifting as endpoint behavior. This paradigm is simple, non-invasive, useful in the assessment of sensory function, and can be adapted to investigate the pharmacokinetics/pharmacodynamics relation of drugs. Further studies are needed to give the conclusive interpretation of the endpoint behavior.
Physiology & Behavior 10/2010; 101(3):327-30. · 2.87 Impact Factor
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ABSTRACT: The P2X(2/3) receptor has an important role in the nociceptive transmission. Minodronic acid is a third third-generation bisphosphonate and a potent inhibitor of bone resorption. We found that minodronic acid inhibited alpha,beta-methylene ATP-induced cation uptake with the potency higher than that of suramin in the P2X(2/3) receptor receptor-expressing cells. Other bisphosphonates did not show such activity. Subcutaneously administered (10-50 mg/kg) minodronic acid significantly inhibited the alpha,beta-methylene ATP-, acetic acid- and formalin-induced nociceptive behaviors in mice. These unique effects of minodronic acid would be beneficial for the treatment of accelerated bone turnover diseases accompanied by bone pain, including bone metastases.
European Journal of Pharmacology 06/2008; 589(1-3):98-101. · 2.52 Impact Factor
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ABSTRACT: Metabotropic glutamate receptor 1 (mGlu(1) receptor) has been suggested to play an important role in pain transmission. In this study, the effects of a newly-synthesized mGlu(1) receptor antagonist, (R)-N-cycloheptyl-6-({[(tetrahydro-2-furyl)methyl]amino}methyl)thieno[2,3-d]pyrimidin-4-ylamine (YM-230888), were examined in a variety of rodent chronic pain models in order to characterize the potential analgesic profile of mGlu(1) receptor blockade. YM-230888 bound an allosteric site of mGlu(1) receptor with a K(i) value of 13+/-2.5 nM and inhibited mGlu(1)-mediated inositol phosphate production in rat cerebellar granule cells with an IC(50) value of 13+/-2.4 nM. It showed selectivity for mGlu(1) versus mGlu(2)-mGlu(7) subtypes and ionotropic glutamate receptors. YM-230888 recovered mechanical allodynia with an ED(50) value of 8.4 mg/kg p.o. in L5/L6 spinal nerve ligation models. It also showed antinociceptive response at doses of 10 and 30 mg/kg p.o. in streptozotocin-induced hyperalgesia models. In addition, it significantly reduced pain parameters at a dose of 30 mg/kg p.o. in complete Freund's adjuvant-induced arthritic pain models. Although YM-230888 showed no significant effect on rotarod performance time at doses of 10 or 30 mg/kg p.o., it significantly decreased it at a dose of 100 mg/kg p.o. On the other hand, YM-230888 showed no significant sedative effect in locomotor activity measurement up to 100 mg/kg p.o. These results suggest that the blockade of mGlu(1) receptors is an attractive target for analgesics. YM-230888 has potential as a new analgesic agent for the treatment of various chronic pain conditions. In addition, YM-230888 may be a useful tool for the investigation of mGlu(1) receptors.
European Journal of Pharmacology 10/2007; 571(1):8-16. · 2.52 Impact Factor
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ABSTRACT: Metabotropic glutamate receptor type 1 (mGluR1) is thought to play important roles in the neurotransmission and pathogenesis of several neurological disorders. Here, we describe the radioligand binding properties and pharmacological effects of a newly synthesized, high-affinity, selective, and noncompetitive mGluR1 antagonist, 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-298198). YM-298198 inhibited glutamate-induced inositol phosphate production in mGluR1-NIH3T3 cells with an IC50 of 16 +/- 5.8 nM in a noncompetitive manner. Its radiolabeled form, [3H]YM-298198, bound to mGluR1-NIH3T3 cell membranes with a KD of 32 +/- 8.5 nM and a Bmax of 2297 +/- 291 fmol/mg protein. In ligand displacement experiments using rat cerebellum membrane, an existing noncompetitive mGluR1 antagonist 7-(hydroxyimino)cyclo-propa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) competitively displaced [3H]YM-298198 binding, although glutamate and other mGluR1 ligands acting on a glutamate site failed to inhibit [3H]YM-298198 binding, suggesting that YM-298198 binds to CPCCOEt (allosteric) binding sites but not to glutamate (agonist) binding sites. Specificity was demonstrated for mGluR1 over mGluR subtypes 2 to 7, ionotropic glutamate receptors, and other receptor, transporter, and ion channel targets. In in vivo experiments, orally administered YM-298198 showed a significant analgesic effect in streptozotocin-induced hyperalgesic mice at doses (30 mg/kg) that did not cause Rotarod performance impairment, indicating that it is also useful even for in vivo experiments. In conclusion, YM-298198 is a newly synthesized, high-affinity, selective, and noncompetitive antagonist of mGluR1 that will be a useful pharmacological tool due to its highly active properties in vitro and in vivo. Its radiolabeled form [3H]YM-298198 will also be a valuable tool for future investigation of the mGluR1.
Journal of Pharmacology and Experimental Therapeutics 11/2005; 315(1):163-9. · 3.83 Impact Factor
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ABSTRACT: The P2X2/3 receptor has an important role in the nociceptive transmission. Minodronic acid is a third third-generation bisphosphonate and a potent inhibitor of bone resorption. We found that minodronic acid inhibited α,β-methylene ATP-induced cation uptake with the potency higher than that of suramin in the P2X2/3 receptor receptor-expressing cells. Other bisphosphonates did not show such activity. Subcutaneously administered (10–50 mg/kg) minodronic acid significantly inhibited the α,β-methylene ATP-, acetic acid- and formalin-induced nociceptive behaviors in mice. These unique effects of minodronic acid would be beneficial for the treatment of accelerated bone turnover diseases accompanied by bone pain, including bone metastases.
European Journal of Pharmacology.
