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.

The results of this study seemed to indicate that the interaction between cannabinoid, COX-2 and NOS(s) systems might exist. Concomitant administration of small doses of CB1 and/or CB2 receptor agonists and COX-2 or NOS inhibitors can be effective in the alleviation of diabetic neuropathic pain.

Depending on the dose used, BK produces pro- or anti-nociceptive action. Both B1 and B2 receptors are involved in the action of icv applied BK.

Taking opioids is often accompanied by the development of dependence. Unfortunately, treatment of opioid dependence is difficult, particularly because of codependence - for example, on alcohol or other drugs of abuse. In the presented study, we analyzed the potential influence of disulfiram, a drug used to aid the management of alcoholism, on opioid abstinence syndrome, which occurs as a result of opioid withdrawal. Opioid dependence in mice was induced by subcutaneous administration of either morphine or methadone at a dose of 48 mg/kg for 10 consecutive days. To trigger a withdrawal syndrome, the opioid receptor antagonist, naloxone, was administered at a dose of 1 mg/kg (subcutaneous), and the severity of withdrawal signs was assessed individually. Interruption of chronic treatment with morphine or methadone by naloxone has led to the occurrence of opioid abstinence signs such as jumping, paw tremor, wet-dog shakes, diarrhea, teeth chattering, ptosis, and piloerection. Importantly, pretreatment with disulfiram (25, 50, and 100 mg/kg) reduced the intensity of withdrawal signs induced by naloxone in morphine or methadone-treated mice. These findings show the effectiveness of disulfiram in reducing opioid abstinence signs.

PurposeAs previously reported, magnesium sulphate administered parenterally significantly increased an opioid antinociception in different kinds of pain. Since the typical form of magnesium salts are poorly and slowly absorbed from the gastrointestinal tract we examined whether their micronized form could increase opioids induced antinociception.MethodsIn behavioural studies on rats morphine, tramadol and oxycodone together with magnesium (lactate dihydrate, hydroaspartate, chloride) in micronized (particles of size D90 < 50 μm) and conventional forms were used. Changes in pain thresholds were determined using mechanical stimuli. The intestinal absorption of two forms of magnesium lactate dihydrate (at the doses of 7.5 or 15 mg ions) in the porcine gut sac model were also compared.ResultsMicronized form of magnesium lactate dihydrate or hydroaspartate but not chloride (15 mg of magnesium ions kg-1) enhanced the analgesic activity of orally administered opioids, significantly faster and more effective in comparison to the conventional form of magnesium salts (about 40% for oxycodone administered together with a micronized form of magnesium hydroaspartate). Moreover, in vitro studies of transport across porcine intestines of magnesium ions showed that magnesium salts administered in micronized form were absorbed from the intestines to a greater extent than the normal form of magnesium salts.ConclusionsThe co-administration of micronized magnesium organic salts with opioids increased their synergetic analgesic effect. This may suggest an innovative approach to the treatment of pain in clinical practice.

High doses of CY-PROLL-SS considerably alleviate peripheral neuropathic pain in model of STZ diabetic neuropathy and CCI. However, mechanisms remain to be elucidated.

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