No abstract

We examined a possible involvement of cyclooxygenase (COX) and nitric oxide synthase (NOS) products in hyperalgesia occurring during streptozotocin (STZ)-induced diabetes. Indomethacin and celecoxib were used as relatively selective inhibitors of COX-1 and COX-2, respectively. NOS inhibitors included: non-specific inhibitor N^G-nitro-L-arginine and L-N⁶-(1-iminoethyl)lysine preferentially acting on inducible NOS (iNOS) as well as 7-nitroindazole relatively specific inhibitor neuronal NOS (nNOS). The above-mentioned agents, except 7-nitroindazole, suppressed hyperalgesia occurring after administration of STZ. The results of the study suggest participation of COX-1, COX-2 and iNOS, but not nNOS, in transmission of pain stimuli in STZ-induced diabetic hyperalgesia.

Streptozotocin-induced hyperglycemia accompanied by a chronic decrease in the nociceptive threshold is considered a useful model of experimental hyperalgesia. We examined (1) the effect of the opioid receptor agonists and (2) the effect of the magnesium ions (Mg²⁺) on the antinociceptive action of opioid agonists in a diabetic neuropathic pain model. When administered alone, opioid agonists like morphine (5 mg/kg i.p.) and fentanyl (0.0625 mg/kg i.p.), as well as the partial agonist buprenorphine (0.075 mg/kg) had only little effect on streptozotocin-induced hyperalgesia. However, pretreatment with Mg²⁺ at a dose of 40 mg magnesium sulfate/kg i.p. markedly enhanced the analgesic activity of all three investigated opioids. Practical aspects of co-administration of magnesium and opioids in diabetic neuropathy are discussed.

The role of bradykinin receptor blockade in the development of neuropathies caused by diabetes mellitus and vincristine was examined. The effects of a potent and selective B₁ receptor antagonist (des-Arg¹⁰-HOE 140) as well as a specific antagonist of B₂ receptors (HOE 140) were investigated. Both agents significantly decreased hyperalgesia caused otherwise by vincristine. In a diabetic neuropathy model, both agents almost completely suppressed hyperalgesia in the first 10 days of the study. However, from day 11 after administration of streptozotocin, the action of des-Arg¹⁰-HOE 140 was significantly weaker than that of HOE 140. The results of the study suggest involvement of both B₁ and B₂ receptors in transmission of nociceptive stimuli in the vincristine-induced as well as diabetic neuropathy model.

Neuropathic pain is difficult to treat. Classic analgesics (i.e., opioid receptor agonists) usually possess low activity. Therefore other agents such as antidepressants, anticonvulsants, and corticosteroids are used. It is commonly known that NMDA antagonists increase analgesic activity of opioids. Unfortunately, clinical use of NMDA antagonists is limited because of the relatively frequent occurrence of adverse effects e.g., memory impairment, psychomimetic effects, ataxia and motor in-coordination. Magnesium ions (Mg(2+)) are NMDA receptor blockers in physiological conditions. Therefore, in this study the effect of opioid receptor agonists and the influence of Mg(2+) on the action of opioid agonists in vincristine-induced hyperalgesia were examined. Opioid agonists such as morphine (5 mg/kg, ip), and fentanyl (0.0625 mg/kg, ip), as well as the partial agonist buprenorphine (0.075 mg/kg, ip) administered alone on 5 consecutives days did not modify the hyperalgesia in vincristine rats. In contrast, pretreatment with a low dose of magnesium sulfate (30 mg/kg, ip) resulted in a progressive increase of the analgesic action of all three investigated opioids. After discontinuation of drug administration, the effect persisted for several days.