Carbamazepine potentiates morphine analgesia on postoperative pain in morphine-dependent rats

Postoperative pain and its control remain one of the most important issues in the field of surgery and health care systems. Morphine is a potent and effective analgesic, but substance abuse patients can manifest crosstolerance to it, making it difficult to satisfy their analgesic/anesthetic requirements. As carbamazepine has shown antinociceptive properties in a variety of experimental and clinical settings, in the present study, we evaluated its potential antiallodynic effects on postoperative pain in naïve and morphine-dependent rats. Male rats were assigned to morphine-dependent and naïve groups and received intraperitoneally drug vehicles as control group, 3 mg/kg morphine, 5, 10 or 15 mg/kg carbamazepine or 5 mg/kg carbamazepine plus 3 mg/kg morphine as a combination therapy 2 and 24 h after surgery. Morphine-dependency was induced with multiple doses of morphine administered i.p. and plantar incision was made on the hind paw to simulate the postoperative pain. Paw withdrawal threshold (PWT) was obtained by von Frey filaments every 30 min after drug injection for up to 180 min. Morphine at 3 mg/kg exerted antiallodynic effects in naïve rats and a decreased antinociception was observed in morphine-dependent rats. In contrast, 5 mg/kg carbamazepine did not significantly alter PWT in naives but it was effective in dependent rats. 10 and 15 mg/kg carbamazepine attenuated allodynia following surgery in both groups. Co-administration of 5 mg/kg carbamazepine with 3 mg/kg morphine produced higher analgesia in morphine-dependent incised rats and prolonged antinociception as compared to morphine alone (Pb0.05). Thus carbamazepine may potentiate the analgesic effect of chronically administered morphine on postoperative pain model in morphinedependent rats

The demyelination and altered motor performance following electrolytic lesion in the ventrolateral white matter of spinal cord in male rats: Benefit of post-injury administration of estradiol

Introduction: Spinal cord injuries are accompanied with significant demyelination of axons and subsequent locomotor dysfunction. To identify the extent of damage following electrolytic lesion of ventrolateral white matter, essential area for initiation of locomotor activity, we assessed demyelination as well as alteration in motor performance. Moreover, the protective effect of estradiol as a candidate treatment for preservation of myelin and locomotor activity after injury was examined due to its antiapoptotic and anti-inflammatory activities. Methods: A unilateral electrolytic lesion positioned in the right ventrolateral funiculus (VLF) was applied following laminectomy at T8-T9. In the estradiol-treated injury group, animals received a pharmacological single dose of estradiol valerate (4 mg/kg) at 30min post injury. Locomotor function was assessed using rotarod and open field tasks during 4 weeks after injury. Results: Obtained results showed significant demyelination at the site of injury and caudal areas following lesion as well as altered motor performance. Post-spinal cord injury administration of estradiol enhanced white matter maintenance at the site of lesion, restored the level of myelin basic protein (MBP), decreased TUNEL positive cells and improved functional recovery. Conclusion: Taken together, these results indicate that demyelination after lesion in VLF may be a contributing factor to limited motor performance, and suggest that pharmacological doses of estradiol may have an early protective effect through sparing of white matter. © 2016, Iranian Society of Physiology and Pharmacology. All rights reserved

Role of Microglia and Astrocyte in Central Pain Syndrome Following Electrolytic Lesion at the Spinothalamic Tract in Rats

Central pain syndrome (CPS) is a debilitating state and one of the consequences of spinal cord injury in patients. Many pathophysiological aspects of CPS are not well documented. Spinal glia activation has been identified as a key factor in the sensory component of chronic pain. In this study, the role of glial subtypes in the process of CPS induced by unilateral electrolytic lesion of spinothalamic tract (STT) is investigated. Male rats received a laminectomy at T8–T9 and then unilateral electrolytic lesion centered on the STT. Thermal and mechanical thresholds as well as locomotor function were measured on days 0, 3, 7, 14, 21, and 28 post-injuries by tail flick, von Frey filament, and open field tests, respectively. To investigate the spinal glial activation following denervation in STT-lesioned groups, Iba1 and GFAP were detected by immunohistochemistry and Western blotting at the same time points. Data showed that STT lesion significantly decreased thermal pain at day 3 in comparison with sham groups. Significant bilateral allodynia appeared in hind paws at day 14 after spinal cord injury and continued to day 28 (P<0.05). Additionally, electrolytic spinal lesion attenuated locomotor function of injured animals after 7 days (P<0.05). In both histological assessments and Western blotting, Iba1 increased at days 3 and 7 while increased GFAP occurred from day 14 to 28 after lesion. It appears that microglial activation is important in the early stages of pain development and astrocytic activation occurs later. These events may lead to behavioral outcomes especially central neuropathic pain

Estradiol attenuates spinal cord injury-induced pain by suppressing microglial activation in thalamic VPL nuclei of rats.

In our previous study we showed that central pain syndrome (CPS) induced by electrolytic injury caused in the unilateral spinothalamic tract (STT) is a concomitant of glial alteration at the site of injury. Here, we investigated the activity of glial cells in thalamic ventral posterolateral nuclei (VPL) and their contribution to CPS. We also examined whether post-injury administration of a pharmacological dose of estradiol can attenuate CPS and associated molecular changes. Based on the results,in the ipsilateral VPL the microglial phenotype switched o hyperactive mode and Iba1 expression was increased significantly on days 21 and 28 post-injury. The same feature was observed in contralateral VPL on day 28 (P<.05). These changes were strongly correlated with the onset of CPS (r(2)=0.670). STT injury did not induce significant astroglial response in both ipsilateral and contralateral VPL. Estradiol attenuated bilateral mechanical hypersensitivity 14 days after STT lesion (P<.05). Estradiol also suppressed microglial activation in the VPL. Taken together, these findings indicate that selective STT lesion induces bilateral microglia activation in VPL which might contribute to mechanical hypersensitivity. Furthermore, a pharmacological dose of estradiol reduces central pain possibly via suppression of glial activity in VPL region

Dicrocoelium dendriticum found in a Bronze Age cemetery in western Iran in the pre-Persepolis period: The oldest Asian palaeofinding in the present human infection hottest spot region

Dicrocoeliasis of animals and humans is caused by trematode species of the genus Dicrocoelium, mainly Dicrocoelium dendriticum in ruminants of the Holarctic region. D. dendriticum may be considered an old parasite, probably related to the appearance and diversification of Eurasian ovicaprines, occurred 14.7-14.5 million years ago. The oldest palaeoparasitological findings of Dicrocoelium in domestic animals and humans date from more than 5000 years BC in Europe. Eggs of D. dendriticum have been found in a burial of a Bronze Age cemetery (2600-2200 BC) close to Yasuj city, southwestern Iran. This is the oldest finding of D. dendriticum in the Near East, where present human infection reports are more numerous than in other world regions where human dicrocoeliasis is rare and sporadic. This palaeofinding in the Zagros mountainous chain area is of interest by its location close to Persepolis, suggesting a narrow relationship between humans and herbivorous animals in these highlands. Domestic ruminant populations of these highlands were following a repeated contact with those of the western flat lowlands of the Fertile Crescent thanks to annual altitudinal transhumance migrations of the nomadic pastoral tribes with their herds living throughout Zagros Mountains in the several millennium period BC. It is concluded that D. dendriticum spread together with sheep and goats westward throughout Europe from the Fertile Crescent during the 8000-6000 year BC period and somewhat later southward into Africa, both spreads facilitated by the low specificity of that trematode species regarding the snail and ant intermediate hosts. (C) 2015 Elsevier Ireland Ltd. All rights reserved

Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy

Impairment of peripheral nerve function is frequent in neurometabolic diseases, but mechanistically not well understood. Here, we report a novel disease mechanism and the finding that glial lipid metabolism is critical for axon function, independent of myelin itself. Surprisingly, nerves of Schwann cell-specific Pex5 mutant mice were unaltered regarding axon numbers, axonal calibers, and myelin sheath thickness by electron microscopy. In search for a molecular mechanism, we revealed enhanced abundance and internodal expression of axonal membrane proteins normally restricted to juxtaparanodal lipid-rafts. Gangliosides were altered and enriched within an expanded lysosomal compartment of paranodal loops. We revealed the same pathological features in a mouse model of human Adrenomyeloneuropathy, preceding disease-onset by one year. Thus, peroxisomal dysfunction causes secondary failure of local lysosomes, thereby impairing the turnover of gangliosides in myelin. This reveals a new aspect of axon-glia interactions, with Schwann cell lipid metabolism regulating the anchorage of juxtaparanodal Kv1-channels

Enhancement of Antinociception by Co-administrations of Nefopam, Morphine, and Nimesulide in a Rat Model of Neuropathic Pain

Background: Neuropathic pain is a chronic pain due to disorder in the peripheral or central nervous system with different pathophysiological mechanisms. Current treatments are not effective. Analgesic drugs combined can reduce pain intensity and side effects. Here, we studied the analgesic effect of nimesulide, nefopam, and morphine with different mechanisms of action alone and in combination with other drugs in chronic constriction injury (CCI) model of neuropathic pain. Methods: Male Wistar rats (n = 8) weighing 150−200 g were divided into 3 different groups: 1- Saline-treated CCI group, 2- Saline-treated sham group, and 3- Drug-treated CCI groups. Nimesulide (1.25, 2.5, and 5 mg/kg), nefopam (10, 20, and 30 mg/kg), and morphine (1, 3, and 5 mg/kg) were injected 30 minutes before surgery and continued daily to day 14 post-ligation. In the combination strategy, a nonanalgesic dose of drugs was used in combination such as nefopam + morphine, nefopam + nimesulide, and nimesulide ＋ morphine. Von Frey filaments for mechanical allodynia and acetone test for cold allodynia were, respectively, used as pain behavioral tests. Experiments were performed on day 0 (before surgery) and days 1, 3, 5, 7,10, and 14 post injury. Results: Nefopam (30 mg/kg) and nimesulide (5 mg/kg) blocked mechanical and thermal allodynia; the analgesic effects of morphine (5 mg/kg) lasted for 7 days. Allodynia was completely inhibited in combination with nonanalgesic doses of nefopam (10 mg/kg), nimesulide (1.25 mg/kg), and morphine (3 mg/kg). Conclusions: It seems that analgesic drugs used in combination, could effectively reduce pain behavior with reduced adverse effects

POTENTIATING EFFECTS OF MORPHINE ANALGESIA WITH CARBAMAZEPINE ON THE POSTOPERATIVE PAIN IN MORPHINE- DEPENDENT RATS

Postoperative pain and its control remains one of the most important issues in the field of surgery and health care system. Morphine is a potent and effective analgesic. But substance abuse patients can manifest cross tolerance to drugs, making it difficult to predict their analgesic or anesthetic requirements. The anticonvulsant drug, carbamazepine (cbz), has many pharmacological effects. In this study we evaluated the effect of various doses of carbamazepine injected Intraperitoneally (i.p.) on postoperative pain in morphine-dependent and naïve rats. Rats were addicted by i.p. morphine. After anesthesia a 1-cm longitudinal incision was made through the skin, fascia and muscle of the plantar aspect of the hind paw and then sutured. Both morphine-dependent and naïve rats received carbamazepine or/and morphine i.p. 2h and 24h after surgery. Paw Withdrawal Threshold by Von Frey Filament obtained every 0.5h after drug injection up to 3h (at surgical day and next day). We saw that the combination of carbamazepine 5mg/kg+morphine 3mg/kg produced more analgesic effects in morphinedependent rats compared to cbz or morphine alone and this combination had same effect of morphine 3mg/kg alone in naïve rats (P<0.05). carbamazepine may potentiate the analgesic effect of chronically administration of morphine

THE ANALGESIC EFFECT OF NIMESULIDE, MORPHINE AND NEFOPAM IN COMBINATION THERAPY IN A RAT MODEL OF NEUROPATHIC PAIN

Neuropathic pain is a chronic pain due to disorder in peripheral or central nervous system and different pathophysiological mechanisms. Currently there is no effective response to conventional therapy. Co-administration of nonanalgesic dose of drugs can reduce both pain and their adverse effects. The goal of this study was to determine the analgesic effect of three drugs (nimesulide, nefopam, morphine) with different mechanisms of action as a single and combination form in a model of neuropathic pain. Neuropathic pain was induced using CCI model in male wistar rats (n=6, 180-220g) and divided into different groups: 1) sham, saline 2) CCI , saline 3) CCI , nimesulide (1.25, 2.5, 5 mg/kg) 4) CCI, nefopam (10, 20, 30 mg/kg) 5) CCI , morphine (1, 3, 5 mg/kg) 6) CCI, nimesulide (1.25 mg/kg)/morphine (3 mg/kg) 7) CCI , nimesulide (1.25 mg/kg)/nefopam (10 mg/kg) 8) CCI , nefopam (10 mg/kg) /morphine (3mg/kg). Pain behavior was assessed using allodynia tests (Vonfrey filaments and acetone test) before and days 1, 5,7,10 and 14 after surgery. The data were analyzed using ANOVA and p<0.05 was considered significant. Morphine, nefopam and nimesulide (5mg/kg, 10 -20mg/kg and 2.5-5mg/kg, respectively) reduced allodynia. The non analgesic doses of drugs reduced pain behavior when used in combination. It seems that analgesic drugs used in combination with low doses controlled pain effectively with less adverse effects seen when they are used alon

Drug Prescription patterns of Physicians in South Khorasan- 2014-2015

Background and Aim:&nbsp; Drug prescription is an important part of pharmacotherapy; therefore, inattention to the principle of drug prescription can cause problems such as incorrect treatment, unsuccessful or incomplete, and force higher cost to patients and society. While prescribing and rational use of drugs can prevent the loss of national capital and community health promotion through improving the quality of life. the goal of this study was to investigate the prescribing indicators of South Khorasan province to determine the level of &nbsp;rational use of drugs. Materials and Methods:&nbsp; In this study, drug prescription data from specialists and general physicians collected from insurance company and analyzed by Rx-analyzer software. Prescibing indicators of all physicians were extracted and evaluated in seprate groups. Results:&nbsp; This study has been done on 1,423,642 insured drug prescriptions collected in South Khorasan province. Indicators showed average number of drug per medical prescription 2.89, the percentage of injectable drugs prescription 33%, the percentage of antimicrobial drugs prescription 42%, the percentage of corticosteroids drugs prescription 20% and precentage of medication prescribed more than 4 drugs 12% were obtained. Also most commonly prescribed drugs to patients are as corticosteroids and antibiotics. Conclusion:&nbsp; Higher drug prescription indicators of South Khorasan especially on corticosteroids and antibiotics percentage in comparison to global data emphasis scientific and educational interventions to promote the principle of rational use of drug