Disulfiram attenuates morphine or methadone withdrawal syndrome in mice.

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.

Micronized Organic Magnesium Salts Enhance Opioid Analgesia in Rats.

PURPOSE: As 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. METHODS: In 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. RESULTS: Micronized 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. CONCLUSIONS: The 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.

Antinociceptive activity of intraperitoneally administered novel and potent anticonvulsive compound, CY-PROLL-SS, in animal neuropathic pain models.

BACKGROUND: Neuropathic pain is still one of the most difficult pain states to be treated due to the lack of effective drugs. Although the mechanism of action of antiepileptic drugs in alleviating neuropathic pain is not fully understood, it is believed that the bases for both diseases are similar pathophysiologic disturbances. Therefore, in this article we explored the analgesic potential of a recently discovered compound CY-PROLL-SS (ADD 408003; 4-phenyl-perhydropyrrole[1,2-a]pyrazine-1,3-dione) with proved anticonvulsant activity. METHODS: CY-PROLL-SS was delivered to animals systemically to assess the antinociceptive effects either in streptozocin (STZ)-induced diabetic or in chronic constriction injury (CCI) models of neuropathic pain after acute exposure to both thermal and mechanical stimulus. RESULTS: Examined here compound dose-dependently reversed thermal and mechanical hyperalgesia induced by STZ single injection. Similar results were obtained for CCI-induced hyperalgesia; however, in this case an attenuation of thermal and reversal of mechanical hyperalgesia were observed. CONCLUSIONS: 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.

Influence of nitric oxide synthase or cyclooxygenase inhibitors on cannabinoids activity in streptozotocin-induced neuropathy.

BACKGROUND: Influence of a relatively specific inhibitor cyclooxygenase (COX)-2, celecoxib, a relatively specific inhibitor of neuronal nitric oxide synthase (NOS), 7-Ni, and a relatively selective inhibitor of inducible NOS, L-NIL, on the action of a preferentially selective CB1 cannabinoid receptor agonist, Met-F-AEA and a selective CB2 cannabinoid receptor agonist, AM 1241 was investigated, in a streptozotocin (STZ)-induced neuropathy. METHODS: Studies were performed on male Wistar rats. Changes in nociceptive thresholds were determined using mechanical stimuli - the modification of the classic paw withdrawal test described by Randall-Selitto. Diabetes was induced by a single administration of STZ. RESULTS: In a diabetic neuropathic pain model, pretreatment with celecoxib, L-NIL and 7-Ni, significantly increased the antihyperalgesic activity of both Met-F-AEA and AM 1241. CONCLUSIONS: 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.

Dose-depending effect of intracerebroventricularly administered bradykinin on nociception in rats.

BACKGROUND: The effect of small and high doses of intracerebroventricularly (icv) applied bradykinin (BK) on nociception produced by mechanical stimuli and the participation of B1 and B2 receptors in this nociception were investigated in rats. RESULTS: BK at the lowest dose (0.06 µg) produced hyperalgesia whereas at the higher doses (6 and 12 µg) antinociception. This effect was abolished by B1 or B2 receptor antagonists, des-Arg(10)-HOE140 and HOE140 (1 pmol icv), respectively. CONCLUSION: 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.

Effect of cyclooxygenase and nitric oxide synthase inhibitors on streptozotocin-induced hyperalgesia in rats.

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-N(6)-(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.