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- Effect of acute and chronic administration of carbamazepine on Cisplatin-induced hyperalgesia in rats. [Journal Article]
- Jundishapur J Nat Pharm Prod 2012; 7(1):27-30.
Cisplatin is an effective antineoplastic drug used extensively in the treatment of malignancies. It induces painful peripheral neuropathy at high doses.The aim of this study was to investigate the effect of carbamazepine (CBZ) on cisplatin-induced peripheral neuropathic pain by using the tail-flick test.The study was performed using male Wistar rats weighing 180-200 g. Neuropathic pain was induced by intraperitoneal (IP) administration of cisplatin (5 mg/kg). The effect of oral (PO) CBZ administration (5, 10, and 15 mg/kg) on cisplatin-induced pain was assessed using the tail-flick test.Our results showed that cisplatin (5 mg/kg, IP) induced egregious pain (P < 0.01) on day 15. Acute administration of CBZ (5, 10, and 15 mg/kg, PO) caused significant (P < 0.05) increase in tail-flick time latency in a dose-dependent manner, in comparison with that observed in the control group. Furthermore, chronic administration of CBZ (5, 10, and 15 mg/kg, PO) increased (P < 0.05) the pain threshold on days 5 and 10. The analgesic effect of morphine (5 mg/kg, IP) was greater than that after acute CBZ administration (5, 10, and 15 mg/kg, PO).Our results showed that both acute and chronic CBZ administration attenuated cisplatin-induced pain. We suggest that CBZ can be used clinically for alleviating cisplatin-induced neuropathic pain in cancer patients, without any limitations such as tolerance to analgesic effect.
- Habituation of the responsiveness of mesolimbic and mesocortical dopamine transmission to taste stimuli. [REVIEW]
- Front Integr Neurosci 2014.:21.
The presentation of novel, remarkable, and unpredictable tastes increases dopamine (DA) transmission in different DA terminal areas such as the nucleus accumbens (NAc) shell and core and the medial prefrontal cortex (mPFC), as estimated by in vivo microdialysis studies in rats. This effect undergoes adaptive regulation, as there is a decrease in DA responsiveness after a single pre-exposure to the same taste. This phenomenon termed habituation has been described as peculiar to NAc shell but not to NAc core and mPFC DA transmission. On this basis, it has been proposed that mPFC DA codes for generic motivational stimulus value and, together with the NAc core DA, is more consistent with a role in the expression of motivation. Conversely, NAc shell DA is specifically activated by unfamiliar or novel taste stimuli and rewards, and might serve to associate the sensory properties of the rewarding stimulus with its biological effect (Bassareo etal., 2002; Di Chiara etal., 2004). Notably, habituation of the DA response to intraoral sweet or bitter tastes is not associated with a reduction in hedonic or aversive taste reactions, thus indicating that habituation is unrelated to satiety-induced hedonic devaluation and that it is not influenced by DA alteration or depletion. This mini-review describes specific circumstances of disruption of the habituation of NAc shell DA responsiveness (De Luca etal., 2011; Bimpisidis etal., 2013). In particular, we observed an abolishment of NAc shell DA habituation to chocolate (sweet taste) by morphine sensitization and mPFC 6-hydroxy-dopamine hydrochloride (6-OHDA) lesion. Moreover, morphine sensitization was associated with the appearance of the habituation in the mPFC, and with an increased and delayed response of NAc core DA to taste in naive rats, but not in pre-exposed animals. The results here described shed light on the mechanism of the habituation phenomenon of mesolimbic and mesocortical DA transmission, and its putative role as a marker of cortical dysfunction in specific conditions such as addiction.
- Selective agonists for serotonin 7 (5-HT7) receptor and their applications in preclinical models: an overview. [JOURNAL ARTICLE]
- Rev Neurosci 2014 Mar 13.
Abstract The serotonin 7 (5-HT7) receptor was the last serotonin receptor subtype to be discovered in 1993. This receptor system has been implicated in several central nervous system (CNS) functions, including circadian rhythm, rapid eye movement sleep, thermoregulation, nociception, memory and neuropsychiatric symptoms and pathologies, such as anxiety, depression and schizophrenia. In 1999, medicinal chemistry efforts led to the identification of SB-269970, which became the gold standard selective 5-HT7 receptor antagonist, and later of various selective agonists such as AS-19, LP-44, LP-12, LP-211 and E-55888. In this review, we summarize the preclinical pharmacological studies performed using these agonists, highlighting their strengths and weaknesses. The data indicate that 5-HT7 receptor agonists can have neuroprotective effects against N-methyl-d-aspartate-induced toxicity, modulate neuronal plasticity in rats, enhance morphine-induced antinociception and alleviate hyperalgesia consecutive to nerve lesion in neuropathic animals.
- Contribution of Adenylyl Cyclase Modulation of Pre- and Postsynaptic GABA Neurotransmission to Morphine Antinociception and Tolerance. [JOURNAL ARTICLE]
- Neuropsychopharmacology 2014 Mar 13.
Opioid inhibition of presynaptic GABA release in the ventrolateral periaqueductal gray (vlPAG) activates the descending antinociception pathway. Tolerance to repeated opioid administration is associated with upregulation of adenylyl cyclase activity. The objective of these studies was to test the hypothesis that adenylyl cyclase contributes to opioid tolerance by modulating GABA neurotransmission. Repeated microinjections of morphine or the adenylyl cyclase activator NKH477 into the vlPAG decreased morphine antinociception as would be expected with the development of tolerance. Conversely, microinjection of the adenylyl cyclase inhibitor SQ22536 reversed both the development and expression of morphine tolerance. These behavioral results indicate that morphine tolerance is dependent on adenylyl cyclase activation. Electrophysiological experiments revealed that acute activation of adenylyl cyclase with forskolin increased the frequency of presynaptic GABA release. However, recordings from rats treated with repeated morphine administration did not exhibit increased basal miniature inhibitory postsynaptic current (mIPSC) frequency but showed a decrease in mean amplitude of mIPSCs indicating that repeated morphine administration modulates postsynaptic GABAA receptors without affecting the probability of presynaptic GABA release. SQ22536 reversed this change in mIPSC amplitude and inhibited mIPSC frequency selectively in morphine tolerant rats. Repeated morphine or NKH477 administration also decreased antinociception induced by microinjection of the GABAA receptor antagonist bicuculline, further demonstrating changes in GABA neurotransmission with morphine tolerance. These results show that the upregulation of adenylyl cyclase caused by repeated vlPAG morphine administration produces antinociceptive tolerance by modulating both pre- and postsynaptic GABA neurotransmission. (Keywords: analgesia, opioid, opiate, GABAA, adenylyl cyclase)Neuropsychopharmacology accepted article preview online, 13 March 2014; doi:10.1038/npp.2014.62.
- Molecular mechanisms underlying the enhanced analgesic effect of oxycodone compared to morphine in chemotherapy-induced neuropathic pain. [Journal Article]
- PLoS One 2014; 9(3):e91297.
Oxycodone is a μ-opioid receptor agonist, used for the treatment of a large variety of painful disorders. Several studies have reported that oxycodone is a more potent pain reliever than morphine, and that it improves the quality of life of patients. However, the neurobiological mechanisms underlying the therapeutic action of these two opioids are only partially understood. The aim of this study was to define the molecular changes underlying the long-lasting analgesic effects of oxycodone and morphine in an animal model of peripheral neuropathy induced by a chemotherapic agent, vincristine. Using a behavioural approach, we show that oxycodone maintains an optimal analgesic effect after chronic treatment, whereas the effect of morphine dies down. In addition, using DNA microarray technology on dorsal root ganglia, we provide evidence that the long-term analgesic effect of oxycodone is due to an up-regulation in GABAB receptor expression in sensory neurons. These receptors are transported to their central terminals within the dorsal horn, and subsequently reinforce a presynaptic inhibition, since only the long-lasting (and not acute) anti-hyperalgesic effect of oxycodone was abolished by intrathecal administration of a GABAB receptor antagonist; in contrast, the morphine effect was unaffected. Our study demonstrates that the GABAB receptor is functionally required for the alleviating effect of oxycodone in neuropathic pain condition, thus providing new insight into the molecular mechanisms underlying the sustained analgesic action of oxycodone.
- Improvement effect of Daikenchuto on morphine-induced constipation through gastrointestinal peptides. [Journal Article]
- Nihon Yakurigaku Zasshi 2014; 143(3):120-5.
- Proteinase-activated Receptor 1 Contributed to Up-regulation of Enkephalin in Keratinocytes of Patients with Obstructive Jaundice. [JOURNAL ARTICLE]
- Anesthesiology 2014 Mar 7.
Skin synthesis of endogenous opioids such as enkephalin is considered to be increased in cholestatic rodents, which may induce antinociception in cholestatic liver disease. No studies have reported yet the expression of skin enkephalin in patients with cholestasis.Electrical pain threshold, postoperative morphine consumption, and skin enkephalin expression were measured in patients with jaundice (n = 18) and control patients (n = 16). Male Sprague-Dawley rats (n = 52) and human keratinocyte cell line HaCaT were used in vivo and in vitro studies, respectively. Nociceptive thresholds and plasma and skin levels of methionine-enkephalin were compared in protease-activated receptors-1-antagonized and control bile duct-ligated rats. In in vitro study, the effect on thrombin-induced enkephalin expression was examined and the role of extracellular regulated protein kinases 1/2 and p38 was investigated.The authors found that: (1) the electrical pain threshold (mean ± SD) was 1.1 ± 0.1 mA in control patients, whereas it was significantly increased in patients with jaundice (1.7 ± 0.3 mA); 48-h postoperative morphine consumption was approximately 50% higher in the control group than that in the group with jaundice; (2) Skin keratinocytes enkephalin expression was increased in the patients with jaundice; (3) Protease-activated receptors-1 antagonist 1 μg·kg·day treatment to the bile duct-ligated rats significantly reduced plasma levels of methionine-enkephalin, nociceptive thresholds, and keratinocytes enkephalin expression; and (4) protease-activated receptors-1 activation induced enkephalin expression through phosphorylation of extracellular regulated protein kinases 1/2 and p38 in keratinocytes.Protease-activated receptors-1 activation in peripheral keratinocytes may play an important role in the local synthesis of enkephalin during cholestasis.
- Degradation of morphine in opium poppy processing waste composting. [JOURNAL ARTICLE]
- Bioresour Technol 2014 Feb 17.
To investigate morphine degradation and optimize turning frequency in opium poppy processing waste composting, a pilot scale windrow composting trial was run for 55days. Four treatments were designed as without turning (A1), every 5days turning (A2), every 10days turning (A3) and every 15days turning (A4). During composting, a range of physicochemical parameters including the residual morphine degradation, temperature, pH, and the contents of total C, total N, total P and total K were investigated. For all treatments, the residual morphine content decreased below the detection limit and reached the safety standards after day 30 of composting, the longest duration of high temperature (⩾50°C) was observed in A3, pH increased 16.9-17.54%, total carbon content decreased 15.5-22.5%, C/N ratio reduced from 46 to 26, and the content of total phosphorus and total potassium increased slightly. The final compost obtained by a mixture of all four piles was up to 55.3% of organic matter, 3.3% of total nutrient (N, P2O5 and K2O) and 7.6 of pH. A turning frequency of every ten days for a windrow composting of opium poppy processing waste is recommended to produce homogenous compost.
- Does midazolam enhance pain control in prehospital management of traumatic severe pain? [JOURNAL ARTICLE]
- Am J Emerg Med 2014 Feb 4.
Midazolam comedication with morphine is a routine practice in pre and postoperative patients but has not been evaluated in prehospital setting. We aimed to evaluate the comedication effect of midazolam in the prehospital traumatic adults.A prehospital prospective randomized double-blind placebo-controlled trial of intravenous morphine 0.10 mg/kg and midazolam 0.04 mg/kg vs morphine 0.10 mg/kg and placebo. Pain assessment was done using a validated numeric rating scale (NRS). The primary end point was to achieve an efficient analgesic effect (NRS ≤ 3) 20 minutes after the baseline. The secondary end points were treatment safety, total morphine dose required until obtaining NRS ≤ 3, and efficient analgesic effect 30 minutes after the baseline.Ninety-one patients were randomized into midazolam (n = 41) and placebo (n = 50) groups. No significant difference in proportion of patients with a pain score ≤ 3 was observed between midazolam (43.6%) and placebo (45.7%) after 20 minutes (P = .849). Secondary end points were similar in regard with proportion of patients with a pain score ≤ 3 at T30, the side effects and adverse events except for drowsiness in midazolam vs placebo, 43.6% vs 6.5% (P < .001). No significant difference in total morphine dose was observed, that is, midazolam (14.09 mg ± 6.64) vs placebo (15.53 mg ± 6.27) (P = .315).According to our study, midazolam does not enhance pain control as an adjunctive to morphine regimen in the management of trauma-induced pain in prehospital setting. However, such midazolam use seems to be associated with an increase in drowsiness.
- Endomorphin analogues with mixed μ-opioid (MOP) receptor agonism/δ-opioid (DOP) receptor antagonism and lacking β-arrestin2 recruitment activity. [JOURNAL ARTICLE]
- Bioorg Med Chem 2014 Feb 24.
Analogues of endomorphin (Dmt-Pro-Xaa-Xaa-NH2) modified at position 4 or at positions 4 and 3, and tripeptides (Dmt-Pro-Xaa-NH2) modified at position 3, with various phenylalanine analogues (Xaa=Trp, 1-Nal, 2-Nal, Tmp, Dmp, Dmt) were synthesized and their effects on in vitro opioid activity were investigated. Most of the peptides exhibited high μ-opioid (MOP) receptor binding affinity (KiMOP=0.13-0.81nM), modest MOP-selectivity (Kiδ-opioid (DOP)/KiMOP=3.5-316), and potent functional MOP agonism (GPI, IC50=0.274-249nM) without DOP and κ-opioid (KOP) receptor agonism. Among them, compounds 7 (Dmt-Pro-Tmp-Tmp-NH2) and 9 (Dmt-Pro-1-Nal-NH2) were opioids with potent mixed MOP receptor agonism/DOP receptor antagonism and devoid of β-arrestin2 recruitment activity. They may offer a unique template for the discovery of potent analgesics that produce less respiratory depression, less gastrointestinal dysfunction and that have a lower propensity to induce tolerance and dependence compared with morphine.