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S142 NUCLEUS RAPHE MAGNUS OPIOID SENSITIVITY TO ANALGESIC EFFECTS OF NSAIDS
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POSTER SESSIONS / European Journal of Pain Supplements 5 (2011) 15–295
group with a non-significant palce-preference (p = 0.11) with an average increase of 96.8 sec. Disclosure: None declared
S141 NANOPARTICLES FROM METALS ENHANCE MORPHINE WITHDRAWAL RESPONSE, BLOOD–BRAIN BARRIER DISRUPTION AND BRAIN PATHOLOGY IN RATS. NEUROPROTECTION BY ONDANSETRON TREATMENT H.S. Sharma1 *, R. Patnaik2 , A. Sharma3 . 1 Surgical Sciences, Anesthesiology, Uppsala University Hospital, Uppsala, Sweden; 2 Biomaterials, Biomedical Engineering, Banaras Hindu University, Inst. Technology, Varanasi, India; 3 Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden Background and Aims: Morphine withdrawal induces blood– brain barrier (BBB) breakdown, brain edema formation and brain pathology in rats. In present investigation we wanted to explore whether engineered nanoparticles from metals, e.g., Cu, Ag or Al could also influence morphine withdrawal induced brain damage in our rat model. Methods: Male Sprague–Dawley rats were treated with Cu, Ag or Al nanoparticles (50–60 nm, 50 mg/kg, i.p.) daily for 1 week. On the day 8th , these rats received morphine (10 mg/Kg, i.p.) once daily for 10 days. Spontaneous withdrawal was precipitated in these rats by abrupt cessation of morphine on day 11th . In separate groups, ondansetron (1 mg or 2 mg/kg, s.c.) was administered from the day of withdrawal once for 3 days. BBB disruption, glial fibrillary acidic protein (GFAP) immunoreactivity, edema formation and neuronal damages were examined in all groups. Results: Morphine withdrawal in nanoparticles treated rats showed an exacerbation in BBB disruption, edema formation, glial cell activation and higher neuronal damage. Interestingly, Ag induces most profound neuronal damages as compared to Cu or Al. Ondansetron (1 mg /kg) pretreatment in normal rats markedly attenuated brain pathology. However, in nanoparticles treated rats 2 mg/kg ondansetron is needed to have the similar neuroprotection. Conclusions: These observations are the first to demonstrate that nanoparticles aggravate morphine withdrawal induced brain pathology and a high dose of ondansetron is needed to reduce brain damage in these rats. Disclosure: None declared
S142 NUCLEUS RAPHE MAGNUS OPIOID SENSITIVITY TO ANALGESIC EFFECTS OF NSAIDS I. Nozadze1 , N. Tsiklauri1 , G. Gurtskaia1 , E. Abzianidze2 , M.G. Tsagareli1 *. 1 Neurophysiology, Beritashvili Institute of Physiology, 2 Medical Genetics, State Medical University of Tbilisi, Tbilisi, Georgia Background and Aims: Our recent investigations have shown that microinjection of NSAIDs into the central nucleus of amygdala, midbrain periaqueductal grey matter and nucleus raphe magnus (NRM) produced tolerance to these drugs and cross-tolerance to morphine. To examine an opioid sensitivity of NSAIDs action we tested on whether post-treatment with m-opioid antagonist naloxone in NRM diminishes NSAID-induced antinociception on the first and second experimental days. Methods: Adult white albino male rats weighing 200–250 g were used in this study. Steel cannula was implanted into NRM and analgin, clodifen, ketorolac, and xefocam were microinjected in the volume of 0.5 ml. The tail flick (TF) and hot plate HP latencies were measured as a parameter of antinociception. Results: Thirty minutes after NSAIDs testing, microinjection of naloxone in NRM significantly decreased antinociceptive effects of NSAIDs at the first day in the TF and HP latencies for analgin, clodifen, ketorolac, and xefocam, respectively. The obtained
data thus confirm evidence for the hypothesis that, like opioids, NSAIDs induce tolerance. The latter should be realized by endogenous opioids, endorphins. Our findings affirm the results of other investigators that microinjection of dipyrone and lysineacetylsalicylate are abolished by systemically injected and/or microinjections of selective m-opioid antagonists, naloxone and CTOP. Conclusions: Taken together our results presented herein and other author’s data strongly suggest that endogenous opioid release plays a crucial role in NSAIDs antinociception and tolerance. On the other hand, our evidence confirms once more that NRM is involved in the descending pain control circuit inhibiting spinal nocifensive reflexes. Disclosure: None declared
S143 THE ANTINOCICEPTIVE EFFECT OF CROTALPHINE, AN OPIOID-LIKE ANALGESIC PEPTIDE, INVOLVES STIMULATION OF PERIPHERAL CANNABINOID RECEPTORS AND ENDOGENOUS OPIOID RELEASE G. Picolo *, F.C. Machado, V.O. Zambelli, A.C.O. Fernandes, Y. Cury. Special Laboratory of Pain and Signaling, Butantan Institute, S˜ ao Paulo, Brazil Background and Aims: Based on the constant search for new analgesic drugs, our group demonstrated that crotalphine, a 14 amino acid-peptide, induces potent and long-lasting analgesic effect mediated by kappa and delta opioid receptors. Nevertheless, in studies of binding, results indicate that crotalphine does not directly activate opioid receptors. Therefore the aim of this work is to evaluate the participation of cannabinoid receptors in the analgesic effect of crotalphine and the possible interaction of these receptors with the opioid system. Methods: Hyperalgesia was induced in rats by prostaglandin E2 (100 ng/paw). The antinociceptive effect of crotalphine (1 mg/kg) was determined using the paw pressure test. The involvement of cannabinoid receptors was investigated using antagonists of these receptors (CB1 , AM251, 80 mg/paw and CB2 , AM630, 50 mg/paw). The participation of endogenous cannabinoid system was evaluated using the irreversible inhibitor of fatty acid amide hydrolase (MAFP, 4 mg/paw). The contribution of endogenous opioids to the antinociception was investigated using antibodies anti-b-endorphin (5 mg/paw), anti-enkephalin (50 mg/paw) and anti-dynorphin A (1 mg/paw) and confirmed by measurement of endogenous opioid release from skin tissue by enzyme immunoassay. Results: CB1 and CB2 receptor antagonists and antibody antidynorphin A inhibited the antinociceptive effect of crotalphine while administration of MAFP enhanced this effect. In vitro enzyme immunoassay confirms that crotalphine induces the local release of dynorphin-A been this effect blocked by CB2 receptor antagonist. Conclusions: Peripheral CB1 and CB2 receptors are involved in antinociception induced by crotalphine. This effect is dependent of dynorphin-A release. Acknowledgements: FAPESP (2009/14203–5, 2010/12917–8) and INCTTOX program (2008/57898-0). Disclosure: None declared
S144 DIFFERENT ACTIONS OF INTRACEREBROVENTRICULAR INJECTION OF MORPHINE AND WIN55212-2 ON URINE OUTPUT OF RAT Z. Mansouri *, N. Nima, M. Fereshteh. Neuroscience Research Center, Shahid Beheshti Medical Science, Tehran, Iran Opioid and cannabinoid receptors have been found both in the hypothalamic regions of brain and in kidneys. Hence, their receptor agonists possibly have pharmacological activity on urine output. Using metabolic cages, the effect of intracerebroventricular (i.c.v.) administration of either opioid receptor agonist morphine or cannabinoid receptor agonist
POSTER SESSIONS / European Journal of Pain Supplements 5 (2011) 15–295
group with a non-significant palce-preference (p = 0.11) with an average increase of 96.8 sec. Disclosure: None declared
S141 NANOPARTICLES FROM METALS ENHANCE MORPHINE WITHDRAWAL RESPONSE, BLOOD–BRAIN BARRIER DISRUPTION AND BRAIN PATHOLOGY IN RATS. NEUROPROTECTION BY ONDANSETRON TREATMENT H.S. Sharma1 *, R. Patnaik2 , A. Sharma3 . 1 Surgical Sciences, Anesthesiology, Uppsala University Hospital, Uppsala, Sweden; 2 Biomaterials, Biomedical Engineering, Banaras Hindu University, Inst. Technology, Varanasi, India; 3 Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden Background and Aims: Morphine withdrawal induces blood– brain barrier (BBB) breakdown, brain edema formation and brain pathology in rats. In present investigation we wanted to explore whether engineered nanoparticles from metals, e.g., Cu, Ag or Al could also influence morphine withdrawal induced brain damage in our rat model. Methods: Male Sprague–Dawley rats were treated with Cu, Ag or Al nanoparticles (50–60 nm, 50 mg/kg, i.p.) daily for 1 week. On the day 8th , these rats received morphine (10 mg/Kg, i.p.) once daily for 10 days. Spontaneous withdrawal was precipitated in these rats by abrupt cessation of morphine on day 11th . In separate groups, ondansetron (1 mg or 2 mg/kg, s.c.) was administered from the day of withdrawal once for 3 days. BBB disruption, glial fibrillary acidic protein (GFAP) immunoreactivity, edema formation and neuronal damages were examined in all groups. Results: Morphine withdrawal in nanoparticles treated rats showed an exacerbation in BBB disruption, edema formation, glial cell activation and higher neuronal damage. Interestingly, Ag induces most profound neuronal damages as compared to Cu or Al. Ondansetron (1 mg /kg) pretreatment in normal rats markedly attenuated brain pathology. However, in nanoparticles treated rats 2 mg/kg ondansetron is needed to have the similar neuroprotection. Conclusions: These observations are the first to demonstrate that nanoparticles aggravate morphine withdrawal induced brain pathology and a high dose of ondansetron is needed to reduce brain damage in these rats. Disclosure: None declared
S142 NUCLEUS RAPHE MAGNUS OPIOID SENSITIVITY TO ANALGESIC EFFECTS OF NSAIDS I. Nozadze1 , N. Tsiklauri1 , G. Gurtskaia1 , E. Abzianidze2 , M.G. Tsagareli1 *. 1 Neurophysiology, Beritashvili Institute of Physiology, 2 Medical Genetics, State Medical University of Tbilisi, Tbilisi, Georgia Background and Aims: Our recent investigations have shown that microinjection of NSAIDs into the central nucleus of amygdala, midbrain periaqueductal grey matter and nucleus raphe magnus (NRM) produced tolerance to these drugs and cross-tolerance to morphine. To examine an opioid sensitivity of NSAIDs action we tested on whether post-treatment with m-opioid antagonist naloxone in NRM diminishes NSAID-induced antinociception on the first and second experimental days. Methods: Adult white albino male rats weighing 200–250 g were used in this study. Steel cannula was implanted into NRM and analgin, clodifen, ketorolac, and xefocam were microinjected in the volume of 0.5 ml. The tail flick (TF) and hot plate HP latencies were measured as a parameter of antinociception. Results: Thirty minutes after NSAIDs testing, microinjection of naloxone in NRM significantly decreased antinociceptive effects of NSAIDs at the first day in the TF and HP latencies for analgin, clodifen, ketorolac, and xefocam, respectively. The obtained
data thus confirm evidence for the hypothesis that, like opioids, NSAIDs induce tolerance. The latter should be realized by endogenous opioids, endorphins. Our findings affirm the results of other investigators that microinjection of dipyrone and lysineacetylsalicylate are abolished by systemically injected and/or microinjections of selective m-opioid antagonists, naloxone and CTOP. Conclusions: Taken together our results presented herein and other author’s data strongly suggest that endogenous opioid release plays a crucial role in NSAIDs antinociception and tolerance. On the other hand, our evidence confirms once more that NRM is involved in the descending pain control circuit inhibiting spinal nocifensive reflexes. Disclosure: None declared
S143 THE ANTINOCICEPTIVE EFFECT OF CROTALPHINE, AN OPIOID-LIKE ANALGESIC PEPTIDE, INVOLVES STIMULATION OF PERIPHERAL CANNABINOID RECEPTORS AND ENDOGENOUS OPIOID RELEASE G. Picolo *, F.C. Machado, V.O. Zambelli, A.C.O. Fernandes, Y. Cury. Special Laboratory of Pain and Signaling, Butantan Institute, S˜ ao Paulo, Brazil Background and Aims: Based on the constant search for new analgesic drugs, our group demonstrated that crotalphine, a 14 amino acid-peptide, induces potent and long-lasting analgesic effect mediated by kappa and delta opioid receptors. Nevertheless, in studies of binding, results indicate that crotalphine does not directly activate opioid receptors. Therefore the aim of this work is to evaluate the participation of cannabinoid receptors in the analgesic effect of crotalphine and the possible interaction of these receptors with the opioid system. Methods: Hyperalgesia was induced in rats by prostaglandin E2 (100 ng/paw). The antinociceptive effect of crotalphine (1 mg/kg) was determined using the paw pressure test. The involvement of cannabinoid receptors was investigated using antagonists of these receptors (CB1 , AM251, 80 mg/paw and CB2 , AM630, 50 mg/paw). The participation of endogenous cannabinoid system was evaluated using the irreversible inhibitor of fatty acid amide hydrolase (MAFP, 4 mg/paw). The contribution of endogenous opioids to the antinociception was investigated using antibodies anti-b-endorphin (5 mg/paw), anti-enkephalin (50 mg/paw) and anti-dynorphin A (1 mg/paw) and confirmed by measurement of endogenous opioid release from skin tissue by enzyme immunoassay. Results: CB1 and CB2 receptor antagonists and antibody antidynorphin A inhibited the antinociceptive effect of crotalphine while administration of MAFP enhanced this effect. In vitro enzyme immunoassay confirms that crotalphine induces the local release of dynorphin-A been this effect blocked by CB2 receptor antagonist. Conclusions: Peripheral CB1 and CB2 receptors are involved in antinociception induced by crotalphine. This effect is dependent of dynorphin-A release. Acknowledgements: FAPESP (2009/14203–5, 2010/12917–8) and INCTTOX program (2008/57898-0). Disclosure: None declared
S144 DIFFERENT ACTIONS OF INTRACEREBROVENTRICULAR INJECTION OF MORPHINE AND WIN55212-2 ON URINE OUTPUT OF RAT Z. Mansouri *, N. Nima, M. Fereshteh. Neuroscience Research Center, Shahid Beheshti Medical Science, Tehran, Iran Opioid and cannabinoid receptors have been found both in the hypothalamic regions of brain and in kidneys. Hence, their receptor agonists possibly have pharmacological activity on urine output. Using metabolic cages, the effect of intracerebroventricular (i.c.v.) administration of either opioid receptor agonist morphine or cannabinoid receptor agonist