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In clinical medicine, morphine is widely used to relieve many types of pain, but it has several side effects such as the development of tolerance and dependence. In order to decrease the side effects of morphine administration for the treatment of pain, the combination of minocycline as a glial inhibitor and morphine has been suggested in previous studies. It is important to understand which synaptic mechanisms are involved in the potentiative effect of minocycline on morphine antinociception. To this aim, male Wistar rats were bilaterally cannulated in the basolateral amygdala by srereotaxic instrument. A tail-flick apparatus was used to measure the pain threshold. The results revealed that intraperitoneal injection of morphine (2.5–7.5 mg/kg) induced antinociception. Intra-basolateral amygdala microinjection of minocycline (5–10 µg/rat) by itself had no effect on tail-flick latency, while the microinjection of the same doses of minocycline with an ineffective dose of morphine (5 mg/kg) induced antinociception. Intra-basolateral amygdala microinjection of different doses of muscimol (0.001–0.005 µg/rat) increased the minocycline-induced potentioation on morphine response in the tail-flick test. Intra-basolateral amygdala microinjection of muscimol by itself had no effect on tail-flick latency. On the other hand, intra-basolateral amygdala microinjection of bicuculline (0.01–0.1 µg/rat) inhibited minocycline-induced potentiation of morphine antinociception. It should be noted that intra-basolateral amygdala bicucculine by itself had no effect on tail-flick latency. It can thus be concluded that intra-basolateral amygdala minocycline potentiates morphine response in the tail-flick test. Moreover, basolateral amygdala GABAergic system may be involved in the minocycline-induced potentiation of morphine response via GABA A receptors. [ABSTRACT FROM AUTHOR]

Abstract: We investigated the effects of intraperitoneal injections of a combination of two cyclo-oxygenase inhibitors, ibuprofen and paracetamol, with a weak opiate, codeine, on nociception in Sprague Dawley rats. Administration of paracetamol (11, 44, and 88mg/kg), ibuprofen (8.75, 35, and 140mg/kg) or codeine (0.44, 1.75, and 3.5mg/kg) alone caused a dose-dependent inhibition of reperfusion hypernociception. Administration of a combination of 0.44mg/kg codeine+8.75mg/kg ibuprofen+11mg/kg paracetamol, drug doses that did not significantly reduce reperfusion hypernociception when administered individually or in pairs, abolished reperfusion hypernociception, such that the antihypernociceptive efficacy of the combination was ∼2.5-fold greater than that of the sum of the antihypernociceptive efficacy of the individual drugs. Coordinated motor function, tested using a rotarod, was not impaired at the doses we used. Thus, we have demonstrated that codeine, paracetamol and ibuprofen act synergistically to induce antihypernociception in rats at doses which do not affect motor function. [Copyright &y& Elsevier]

Abstract: Lack of involvement of the opioid system with the endocannabinoid, arachidonylethanolamide (anandamide) was possibly due to hydrolysis by fatty acid amide hydrolase (FAAH). Cyclohexylcarbamic acid 3′-carbamoyl-biphenyl-3-yl ester (URB597) is an inhibitor of FAAH, increases brain anandamide levels and enhances anandamide-induced antinociception in male ICR mice (25–30 g). The combination of URB597 (10 mg/kg, i.p.) and anandamide (40 mg/kg, i.p.) produced maximal antinociception in the mouse tail-flick test [68.7±16.8 percent maximum possible effect (%MPE)], versus either substance alone (27.3±7.9%MPE and 4.6±2.3%MPE, respectively) and is significantly blocked (p <0.05) by the cannabinoid CB1 receptor antagonist, SR141716A (rimonabant), the kappa opioid receptor-selective antagonist, nor-Binaltorphimine (10 μg i.t.; 12.7±4.0%MPE) and the mu opioid receptor antagonist, naloxone (1 mg/kg, s.c.; 6.0±3.8%MPE), but not by the delta opioid receptor-selective antagonist, naltrindole (2 mg/kg, s.c.; 29.7±8.2%MPE) or the cannabinoid CB2 receptor antagonist, SR144528. In addition, nor-BNI (10 μg i.t) administration to FAAH−/− knockout mice produced a nociceptive response. The URB597/anandamide combination was not active in the CB1 −/− knockout mice, but retained activity in the MOR−/− knockout mice. The sub-active combination of (URB597 10 mg/kg, i.p/anandamide 10 mg/kg, i.p.; 15.5±4.3%MPE) shifted the dose response curve of morphine to the left (morphine alone ED50 =4.6 mg/kg [3.7–5.6] versus morphine/URB597/anandamide (ED50 =2.5 mg/kg [1.9–3.4]). These data are the first demonstration that anandamide, if protected from degradation, acts via the CB1 receptor to interact with kappa opioid receptor systems in opioid analgesia. [Copyright &y& Elsevier]

Abstract: Neuropathy accompanied by abnormal sensory perception is the most common complication in insulin-dependent and -independent diabetes mellitus. Since there are very few effective therapeutic regimens for sensory abnormalities in diabetes, we examined the effect of cytidine 5′-diphosphocholine (CDP)-choline on the thermal nociceptive threshold in streptozotocin-induced diabetic mice using the tail-flick test. Diabetic mice showed a shorter tail-flick latency at 1–4 weeks after streptozotocin treatment and a longer tail-flick latency after 8–12 weeks. This hyper- and hypoalgesia in diabetic mice was almost completely inhibited by daily treatment with CDP-choline (100mg/kg/day, p.o.) beginning on the day of streptozotocin treatment. Daily treatment with CDP-choline beginning 5 weeks after streptozotocin treatment attenuated the development of hypoalgesia. Diabetic mice showed a significant increase in Na+-K+-ATPase activity at 3 weeks after streptozotocin treatment, whereas Na+-K+-ATPase activity was decreased at 12 weeks after treatment. These alterations were normalized by daily treatment with CDP-choline (100mg/kg/day, p.o.) beginning the day of streptozotocin treatment. These results provide evidence to support the therapeutic potency of CDP-choline on the development of thermal hyper- and hypoalgesia and the progression of thermal hypoalgesia in diabetic mice. Moreover, these effects of CDP-choline may result from the normalization of Na+-K+-ATPase activity. [Copyright &y& Elsevier]

Nitroglycerin is a nitric oxide (NO) donor which activates nuclei involved in nociceptive transmission following systemic administration. The effect of nitroglycerin on the nociceptive threshold was studied in rats by means of two experimental tests that explore different modalities of pain: the tail-flick test and the formalin test. Nitroglycerin induced a significant reduction in the latency of the tail flick 2 and 4 h after its administration. Similarly, formalin-induced pain-related behaviour increased significantly 2 and 4 h after nitroglycerin administration. [Copyright &y& Elsevier]

The goal of this study was to investigate the effects of endomorphin-1 on Na+,K+-ATPase activity in mouse brain synaptosome in vitro, and its antinociceptive interaction with the Na+,K+-ATPase inhibitor ouabain. Endomorphin-1 (0.1 nM–10 μM) produced a concentration-dependent (EC50: 43.19 nM, CI: 23.38–65.71 nM, Emax: 25.86%, CI: 24.53–27.20%), naloxone-reversible increase of the synaptosomal Na+,K+-ATPase activity. The intrathecally (i.t.) administered endomorphin-1 (2–20 μg) produced a dose-dependent short-lasting increase in the tail-flick latency. Ouabain itself (1–1000 ng, i.t.) did not cause antinociception. Treatment with 10 ng ouabain significantly decreased the antinociceptive effect of 2 μg endomorphin-1, but none of the other combinations did significantly differ from the endomorhin-1-treated groups. These data indicate that endomorphin-1 increases the activity of Na+,K+-ATPase in vitro but this effect may play a weak role in the antinociception induced by intrathecal endomorphin-1. [Copyright &y& Elsevier]

The Ca2+ channel blocker, nimodipine, increases the chronic naltrexone-induced supersensitivity to morphine analgesia in mice without affecting the density of up-regulated μ-opioid receptors. In the present study, the change in dihydropyridine-sensitive Ca2+ channels associated with chronic naloxone-induced supersensitivity to morphine analgesia was studied in rat whole-brain membranes using a radiolabeled Ca2+ channel blocker, [3H]PN200-110 {isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonylpyridine-3-carboxylate} (0.02–1.0 nmol/l). Rats were chronically treated with naloxone (1 mg/kg, i.p.), nimodipine (1 mg/kg, i.p.) or their respective vehicles twice daily for 10 days. On the 11th day, 16 h after the last injection of either nimodipine or naloxone, morphine (2 mg/kg, i.p.)-induced tail-flick analgesia was determined or rats were killed for the binding study. Chronic naloxone significantly potentiated (+84%) the morphine-induced analgesia. Chronic nimodipine also potentiated (+76%) morphine analgesia. In rats treated with nimodipine and naloxone, there was an additive increase (206%) in morphine analgesia. In binding studies, chronic naloxone resulted in a significant decrease (−39%) in the density (Bmax) of [3H]PN200-110 binding with no change in Kd value when compared to the effect of chronic vehicle. Chronic nimodipine resulted in a slight but significant (+14.5%) increase in the Bmax of [3H]PN200-110. However, when nimodipine was co-administered with naloxone, it not only reversed the down-regulation but actually up-regulated (+25%) [3H]PN200-110 binding with no change in Kd value. Our results show significant down-regulation of [3H]PN200-110 binding in association with naloxone-induced analgesic supersensitivity to morphine. The supersensitivity was also observed following chronic blockade of up-regulated Ca2+ channels by nimodipine. These results indicate an important role of L-type Ca2+ channel regulation in naloxone-induced analgesic supersensitivity to morphine. [Copyright &y& Elsevier]

The effect of the pretreatment with endomorphin-1 or endomorphin-2 given into anterior 4th ventricle (i.vt.) on the antinociception with the tail-flick test induced by subsequent intraventricular (i.vt.) injection of endomorphin-1 or endomorphin-2were studied in rats. The i.vt. pretreatment with 30 nmol of endomorphin-1 or 60 nmol of endomorphin-2 developed an antinociceptive tolerance to the subsequently challenging dose of i.vt.-administered endomorphin-1 or endomorphin-2, respectively, with different time courses. The endomorphin-1-induced antinociceptive tolerance reached a maximal level at 2 h, recovered slowly in 24 h after the pretreatment with endomorphin-1, whereas endomorphin-2-induced antinociceptive tolerance developed in 1 h and recovered in 4 h. Rats made tolerant to endomorphin-1 by i.vt. pretreatment with endomorphin-1 exhibited nearly no cross-tolerance to endomorphin-2 to produce antinociception. On the other hand, rats made tolerant to endomorphin-2 exhibited a complete cross-tolerance to endomorphin-1 to produce antinociception. We propose that different degrees of receptor endocytosis for receptor inactivation after stimulation of μ-opioid receptors by endomorphin-1 and endomorphin-2 and/or two separate subtypes of μ-opioid receptors are involved in the antinociception induced by endomorphin-1 and endomorphin-2. [Copyright &y& Elsevier]