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Characterization of a rat and mouse formalin model of spontaneous nociceptive behaviors
Abstracts
anticonvulsant agents. The goal of the present study was to evaluate the putative proconvulsant effect of UCB-xyz, a CNS-targeted drug with a novel mechanism of action. The plasma concentration of PTZ was also measured in order to take into account any effect due to potential pharmacokinetic drug–drug interaction between UCB-xyz and PTZ. PTZ was infused into the tail vein of Wistar rats following oral treatment with UCB-xyz (3, 10 and 30 mg/kg) either acutely or for 7 days. UCB-xyz dose-dependently decreased the threshold dose of PTZ which induced clonic seizures, reaching a maximal effect of approximately 30% versus vehicle at 10 mg/kg after both acute and repeated UCB-xyz administration. PTZ plasma concentrations measured just after PTZ infusion linearly correlated with the PTZ dose administered. When PTZ plasma levels were “normalized” for the PTZ dose, they appeared roughly similar across treatment groups, with no evidence of relationship with UCB-xyz dose. This suggests the absence of a pharmacokinetic interaction between PTZ and the test compound. In conclusion, UCB-xyz displayed a proconvulsant activity in the rat PTZ infusion seizure test. Concomitant determination of PTZ plasma exposure allowed ruling out any co-dosing effects through pharmacokinetic interactions of UCB-xyz with PTZ, which could have led to misinterpretation of the proconvulsant effects of the test compound. doi:10.1016/j.vascn.2013.01.026
e5
effects of known neurotoxicants on the CNS at Pharmaron's Toxicology and Safety Pharmacology facility. The FOB includes observations in the home cage, hand-held or using a chair and open field, elicited responses, grip strength, landing foot splay distance, body temperature and weight. In Sprague–Dawley rats, acrylamide (60 mg/kg i.p. for nine days), methanol (6 mL/kg p.o. for three days), chlorpromazine (5 mg/kg i.p.), and carbaryl (90 mg/kg p.o.), induced inhibitory CNS effects, including abnormal posture, low arousal, uncoordinated movement, decreased grip strength and body temperature and increased landing foot splay distance. Permethrin (90 mg/kg oral) induced high arousal. Triadimefon (100 mg/kg p.o.) induced high arousal and increased locomotor activity. In CD-1 mice, carbaryl (150 mg/kg p.o.) induced abnormal posture, low arousal, uncoordinated movement, tremors, lacrimation, salivation, loss of approach and tail pinch response, and decreased rearing, locomotor activity, grip strength and body temperature. Scopolamine (4 mg/kg, i.p.) induced high arousal and locomotor activity and decreased grip strength. In cynomolgus monkeys, ketamine (5.6 mg/kg, i.m.) induced abnormal posture, low arousal, decreased locomotor activity, vocalization, slow respiration, uncoordinated movement, loss of proprioception, dysmetria, and decreased body temperature. Amphetamine (3.2 mg/kg, p.o.) increased locomotor activity, and induced positive Chaddock and Babinski reflexes. These observed neurobehavioral effects are similar and/or comparable to the results reported in the literature. In conclusion, the FOB assessment for potential neurotoxicity screening in rodents and nonhuman primates is validated at Pharmaron.
014 doi:10.1016/j.vascn.2013.01.028 Characterization of a rat and mouse formalin model of spontaneous nociceptive behaviors Giuseppina Iacono, Kevin Norton Charles River Laboratories, Senneville, QC, Canada The rodent formalin model has been proposed as an acute model for evaluating the potential analgesic effects of novel chemical entities on nociceptive behaviors. The purpose of this current study was to characterize the time course of formalin evoked spontaneous nociceptive behaviors in both mice and rats and confirm that known analgesics reduced the formalin evoked responses. Animals received a single intraplantar injection of formalin and nociceptive behaviors were evaluated for up to 60 min post injection. Behaviors were characterized into three discrete areas: flinching, licking of paw or self biting. In rats assessments were conducted by counting the incidence of each behavior while in mice the duration of each behavior was assessed. In both species administration of formalin resulted in a two discrete phase of nociceptive behaviors, with initial effects noted within the first 5 min and a second period of response occurred within 15 to 60 min following administration. Administration of morphine or mexiletine, 30 min and 1 h prior to formalin administration respectively, resulted in a dose dependent decrease of behaviors, in both phases, confirming that this model does provide an acute screening model for evaluating the potential effects of analgesics. doi:10.1016/j.vascn.2013.01.027
015 Method validation of functional observational battery assessment in rodents and nonhuman primates Yujuan Li, Na Niu, Qing Cai Pharmaron, Inc., Beijing, China The effects of a test substance on the central nervous system (CNS) are evaluated in a functional observational battery (FOB) to evaluate the
016 Characterization of neurobehavioral changes following mild traumatic brain injury in male Sprague–Dawley rats Kristy Brusea,b, Yung Sung Chenga, Hammad Irshada, Michael Weisendb, Andrew Mayerb a
Lovelace Respiratory Research Institute, Albuquerque, NM, USA Mind Research Network, Albuquerque, NM, USA
b
The objective of this pilot study was to characterize the neurobehavioral and mnemonic effects of blast-related mild traumatic brain injury (mTBI). Adult male SD rats were tested prior to and following mTBI in a within subjects design. Three groups were assessed: sham treatment (n= 4), blast pressure plus tertiary injuries, achieved through minimal restraint, (BP + TI; n = 2) and blast pressure using a full restraint (BP; n = 3). Assessments included a modified Functional Observational Battery (FOB), an inverted screen (IS), rotor-rod (RR), and the Morris Water Task (MWT). Animals were anesthetized (Avertin, 300 mg/kg, IP) and placed into a custom built rodent restrainer and placed next to the blast tube. The rat and restrainer were positioned parallel to the floor such that the right lateral head was in front of the blast tube while the body remained outside the tube. The blast tube generated a peak pressure of 13.7 ± 0.5 PSI measured near the head of the rat. Compared to Sham and BP, BP + TI animals stayed on the Rotor-Rod for a shorter period and righted themselves on the inverted screen more slowly on post-blast days 5 and 3, respectively. In the MWT, sham, BP, and BP+ TI rats performed similarly prior to blast. However, after blast BP + TI rats took longer to swim to a visible platform, showed slower intra-day place learning and low place persistence relative to the sham and BP groups after injury. Basic neurobehavioral/learning and memory tasks are useful in understanding the sequelae of mTBI elicited by blast pressure with or without tertiary injury. doi:10.1016/j.vascn.2013.01.029
anticonvulsant agents. The goal of the present study was to evaluate the putative proconvulsant effect of UCB-xyz, a CNS-targeted drug with a novel mechanism of action. The plasma concentration of PTZ was also measured in order to take into account any effect due to potential pharmacokinetic drug–drug interaction between UCB-xyz and PTZ. PTZ was infused into the tail vein of Wistar rats following oral treatment with UCB-xyz (3, 10 and 30 mg/kg) either acutely or for 7 days. UCB-xyz dose-dependently decreased the threshold dose of PTZ which induced clonic seizures, reaching a maximal effect of approximately 30% versus vehicle at 10 mg/kg after both acute and repeated UCB-xyz administration. PTZ plasma concentrations measured just after PTZ infusion linearly correlated with the PTZ dose administered. When PTZ plasma levels were “normalized” for the PTZ dose, they appeared roughly similar across treatment groups, with no evidence of relationship with UCB-xyz dose. This suggests the absence of a pharmacokinetic interaction between PTZ and the test compound. In conclusion, UCB-xyz displayed a proconvulsant activity in the rat PTZ infusion seizure test. Concomitant determination of PTZ plasma exposure allowed ruling out any co-dosing effects through pharmacokinetic interactions of UCB-xyz with PTZ, which could have led to misinterpretation of the proconvulsant effects of the test compound. doi:10.1016/j.vascn.2013.01.026
e5
effects of known neurotoxicants on the CNS at Pharmaron's Toxicology and Safety Pharmacology facility. The FOB includes observations in the home cage, hand-held or using a chair and open field, elicited responses, grip strength, landing foot splay distance, body temperature and weight. In Sprague–Dawley rats, acrylamide (60 mg/kg i.p. for nine days), methanol (6 mL/kg p.o. for three days), chlorpromazine (5 mg/kg i.p.), and carbaryl (90 mg/kg p.o.), induced inhibitory CNS effects, including abnormal posture, low arousal, uncoordinated movement, decreased grip strength and body temperature and increased landing foot splay distance. Permethrin (90 mg/kg oral) induced high arousal. Triadimefon (100 mg/kg p.o.) induced high arousal and increased locomotor activity. In CD-1 mice, carbaryl (150 mg/kg p.o.) induced abnormal posture, low arousal, uncoordinated movement, tremors, lacrimation, salivation, loss of approach and tail pinch response, and decreased rearing, locomotor activity, grip strength and body temperature. Scopolamine (4 mg/kg, i.p.) induced high arousal and locomotor activity and decreased grip strength. In cynomolgus monkeys, ketamine (5.6 mg/kg, i.m.) induced abnormal posture, low arousal, decreased locomotor activity, vocalization, slow respiration, uncoordinated movement, loss of proprioception, dysmetria, and decreased body temperature. Amphetamine (3.2 mg/kg, p.o.) increased locomotor activity, and induced positive Chaddock and Babinski reflexes. These observed neurobehavioral effects are similar and/or comparable to the results reported in the literature. In conclusion, the FOB assessment for potential neurotoxicity screening in rodents and nonhuman primates is validated at Pharmaron.
014 doi:10.1016/j.vascn.2013.01.028 Characterization of a rat and mouse formalin model of spontaneous nociceptive behaviors Giuseppina Iacono, Kevin Norton Charles River Laboratories, Senneville, QC, Canada The rodent formalin model has been proposed as an acute model for evaluating the potential analgesic effects of novel chemical entities on nociceptive behaviors. The purpose of this current study was to characterize the time course of formalin evoked spontaneous nociceptive behaviors in both mice and rats and confirm that known analgesics reduced the formalin evoked responses. Animals received a single intraplantar injection of formalin and nociceptive behaviors were evaluated for up to 60 min post injection. Behaviors were characterized into three discrete areas: flinching, licking of paw or self biting. In rats assessments were conducted by counting the incidence of each behavior while in mice the duration of each behavior was assessed. In both species administration of formalin resulted in a two discrete phase of nociceptive behaviors, with initial effects noted within the first 5 min and a second period of response occurred within 15 to 60 min following administration. Administration of morphine or mexiletine, 30 min and 1 h prior to formalin administration respectively, resulted in a dose dependent decrease of behaviors, in both phases, confirming that this model does provide an acute screening model for evaluating the potential effects of analgesics. doi:10.1016/j.vascn.2013.01.027
015 Method validation of functional observational battery assessment in rodents and nonhuman primates Yujuan Li, Na Niu, Qing Cai Pharmaron, Inc., Beijing, China The effects of a test substance on the central nervous system (CNS) are evaluated in a functional observational battery (FOB) to evaluate the
016 Characterization of neurobehavioral changes following mild traumatic brain injury in male Sprague–Dawley rats Kristy Brusea,b, Yung Sung Chenga, Hammad Irshada, Michael Weisendb, Andrew Mayerb a
Lovelace Respiratory Research Institute, Albuquerque, NM, USA Mind Research Network, Albuquerque, NM, USA
b
The objective of this pilot study was to characterize the neurobehavioral and mnemonic effects of blast-related mild traumatic brain injury (mTBI). Adult male SD rats were tested prior to and following mTBI in a within subjects design. Three groups were assessed: sham treatment (n= 4), blast pressure plus tertiary injuries, achieved through minimal restraint, (BP + TI; n = 2) and blast pressure using a full restraint (BP; n = 3). Assessments included a modified Functional Observational Battery (FOB), an inverted screen (IS), rotor-rod (RR), and the Morris Water Task (MWT). Animals were anesthetized (Avertin, 300 mg/kg, IP) and placed into a custom built rodent restrainer and placed next to the blast tube. The rat and restrainer were positioned parallel to the floor such that the right lateral head was in front of the blast tube while the body remained outside the tube. The blast tube generated a peak pressure of 13.7 ± 0.5 PSI measured near the head of the rat. Compared to Sham and BP, BP + TI animals stayed on the Rotor-Rod for a shorter period and righted themselves on the inverted screen more slowly on post-blast days 5 and 3, respectively. In the MWT, sham, BP, and BP+ TI rats performed similarly prior to blast. However, after blast BP + TI rats took longer to swim to a visible platform, showed slower intra-day place learning and low place persistence relative to the sham and BP groups after injury. Basic neurobehavioral/learning and memory tasks are useful in understanding the sequelae of mTBI elicited by blast pressure with or without tertiary injury. doi:10.1016/j.vascn.2013.01.029