6-cyano-7-nitroquinoxaline-2-3-dione and 7-7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one

Current single drug treatments for rheumatoid arthritis have problems of limited efficacy and/or high toxicity. This study investigates the benefits of individual and combined treatments with dexamethasone and substance P and glutamate receptor antagonists in a rat model of arthritis.. Arthritis was induced in rats by unilateral intra-articular injection of Freund's complete adjuvant. Separate groups of rats were subjected to the following treatments 15 min before induction of arthritis: (i) control with no drug treatment; (ii) single intra-articular injection of a NK(1) receptor antagonist RP67580; (iii) single intra-articular injection of a NMDA receptor antagonist AP7 plus a non-NMDA receptor antagonist CNQX; (iv) daily oral dexamethasone; and (v) combined treatment with dexamethasone and all of the above receptor antagonists. Knee joint allodynia, swelling, hyperaemia and histological changes were examined over a period of 7 days.. Treatment with dexamethasone suppressed joint swelling, hyperaemia and histological changes that include polymorphonuclear cell infiltration, synovial tissue proliferation and cartilage erosion in the arthritic rat knees. Treatment with RP67580 or AP7 plus CNQX did not attenuate hyperaemia or histological changes, but reduced joint allodynia and swelling. Co-administration of dexamethasone with these receptor antagonists produced greater inhibition on joint allodynia and swelling than their individual effects.. The data suggest substance P and glutamate contribute to arthritic pain and joint swelling. The efficacy of dexamethasone in reducing arthritic pain and joint swelling can be improved by co-administration of substance P and glutamate receptor antagonists.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Dexamethasone; Drug Interactions; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Freund's Adjuvant; Glutamic Acid; Injections, Intra-Articular; Isoindoles; Knee Joint; Neurokinin-1 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Receptors, Neurokinin-1; Substance P; Time Factors

We investigated the effect of topical application of capsaicin cream on withdrawal latency in the hind foot of rat in response to radiant heat in an experimental model of neuropathic pain. A neuropathic state was induced by loose ligation of the sciatic nerve with chromic gut suture. A marked thermal hyperalgesia was observed in response to heat stimulus applied to the operated side from 3 days through 2 weeks, followed by a gradual return to the control level by 35 days after surgery. Capsaicin cream applied to both the bilateral hind instep and sole once a day for a continuous period of 2 weeks or 4 weeks alleviated thermal hyperalgesia in a dose-dependent manner. A remarkable effect was observed 2 weeks after the start of the application and this effect proved to be reversible. On the other hand, in sham-operated animals when capsaicin cream was applied once daily from day 7 after the sham operation, from 1 day through 3 weeks following capsaicin application, withdrawal latency of the sham-operated paws of the capsaicin-treated group was significantly increased as compared to that of the vehicle cream-treated group. The effects of antagonists of glutamate receptor and tachykinin receptors were investigated 7 days post surgery. Pretreatment with MK-801 (0.5 mg kg(-1), i.p.), but not with CNQX (0.5 mg kg(-1), i.p.), reversed the thermal hyperalgesia following nerve injury. Neither of RP67580 (1--10 mg kg(-1), i.p.) nor SR48968 (1--10 mg kg(-1), i.p.) had any effect on the withdrawal latency in the injured and non-injured hind paw. These results suggest that although the manifestation of effectiveness may be delayed by changes in networks of neurotransmitters related to the nociceptive pathways following nerve injury, longer-term repetitive application of capsaicin cream has a significant therapeutic effect on subjects with painful peripheral neuropathy.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Analgesics; Animals; Benzamides; Capsaicin; Carrageenan; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hyperalgesia; Indoles; Isoindoles; Male; Neuroprotective Agents; Pain; Peripheral Nervous System Diseases; Piperidines; Postoperative Period; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Substance Withdrawal Syndrome; Time Factors