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(666)
S22
Abstracts
(665) Cannabinoid agonist WIN55,212-2 suppresses opioidinduced pruritus in mice
(667) Bicifadine is an efficacious analgesic in animal models of neuropathic pain
H Lee, M Ko, S Oh, K Shin; Korea University, College of Medicine, Seoul, Korea Cannabinoid receptor agonists receptor can reversed opioid-induced nausea, vomiting in animals but have not been tested against opioidinduced pruritus yet. This study tests the hypothesis that cannabinoid receptor agonist will prevent opioid-induced pruritus and also tests that cannabinoid receptor agonist will increase the analgesic efficacy of opioids in that dose range. Male ICR mice, 20-25 g, were used. All drugs were injected subcutaneously. For getting the dose-response curve of fentanyl by writhing test, acetic acid (0.6%, 0.4 ml, i.p.) was injected 5 minute prior to 10 minute observation period. Various doses of fentanyl (vehicle, 0.001, 0.0032, 0.01, 0.032, 0.1 mg/kg, 10 ml/kg) were pretreated 15 min earlier. To observe analgesic potentiation of WIN55,212-2 in writhing test, various concentration of WIN55,212-2 (0.25, 0.5, 1.0, 2.0 mg/kg, 10 min PT) were pretreated 10 minutes earlier than the injection of ED50 dose of fentanyl from previous dose-response curve. To observe antipruritogenic effect of WIN55,212-2 in scratching test, various dose of WIN55,212-2 (0.25, 0.5 mg/kg) were pretreated 20 minutes earlier than fentanyl injection. AM251 (3 mg/kg) was used to confirm receptor selectivity. The ED50 of fentanyl in writhing test was 0.018 (0.011-0.025) mg/kg. WIN55,212-2, 1 mg/kg, can increase the analgesic efficacy of fentanyl significantly (p ⬍ 0.01) but not 0.25, 0.5 mg/kg. WIN55,212-5, 0.25 mg/kg can reduce the scratching responses of fentanyl significantly (p ⬍ 0.01) and these were receptor selective. These results demonstrate that WIN55,212-2, 0.25 mg/kg, can prevents opioid-induced pruritus and the antipruritogenic activity of WIN55,212-2 occurs at CB1 receptors even if analgesic efficacy of fentanyl cannot be increased in that dose.
A Basile, E Koustova, A Lippa, P Skolnick; DOV Pharmaceutical, Inc, Hackensack, NJ Bicifadine (DOV 220,075), a balanced inhibitor of norepinephrine and serotonin uptake, was evaluated in two models of neuropathic pain: streptozotocin-induced diabetic neuropathy, and the spinal nerve ligation (SNL) model (Kim and Chung, 1992). In the diabetic neuropathy model, the effect of bicifadine on the paw pressure withdrawal threshold was determined using the Randall-Selitto test. Bicifadine’s efficacy in reducing mechanical allodynia in the SNL model was measured using Semmes-Weinstein filaments and its effects on mechanical and thermal hyperalgesia were evaluated with the Randall-Selitto test and a focused beam of infrared radiation, respectively. Bicifadine dose-dependently reduced the nociceptive threshold for paw withdrawal in diabetic rats (ED50 ⫽ 5 mg/kg PO). Similarly, bicifadine reduced mechanical allodynia in the SNL model, with a maximum anti-allodynic action observed at 40mg/kg PO, an effect comparable in magnitude to 300 mg/kg PO of gabapentin. In addition, bicifadine induced anti-mechanical (ED50 ⫽ 12 mg/kg PO) and thermal (MED 12.5 mg/kg PO) hyperalgesic effects. The effect of bicifadine in blocking mechanical hyperalgesia in the SNL model reached a maximum at 60 minutes and remained significant up to 120 minutes after administration. Its effects in blocking thermal hyperalgesia reached a maximum at 30 minutes and lasted up to 240 minutes after administration. Chronic administration (50mg/kg/day, 5 days, PO) of bicifadine did not result in the development of analgesic tolerance, with efficacy in reducing mechanical hyperalgesia in SNL rats similar to acute bicifadine (50mg/kg). In contrast, repeated administration of morphine (128 mg/kg/D, 5 days, PO) resulted in a significant reduction in efficacy. In conclusion, bicifadine is a potent and efficacious analgesic in two well-described models of neuropathic pain, and exhibits no abuse potential.
(666) Bicifadine: Characterization of its molecular pharmacology and efficacy in animal models of acute pain
(668) Peripheral analgesic effect of ketamine
E Koustova, A Basile, A Lippa, P Skolnick; DOV Pharmaceutical, Inc, Hackensack, NJ Bicifadine (DOV 220,075) is a balanced inhibitor of norepinephrine and serotonin uptake (IC50 ⫽ 55⫾3, 117⫾26 nM, respectively) which exhibits no significant affinity for , , and ␦ opioid receptor subtypes as well as a host of other receptors/ion channels/enzymes, including the NMDA, nicotinic and muscarinic cholinergic, vanilloid, orphanin, NK and cannabinoid receptors, voltage-gated sodium, potassium and N-type calcium channels, and COX1, COX2. This profile suggests that the primary molecular mechanism responsible for analgesic actions of bicifadine relates to its ability to modulate monoaminergic neurotransmitter pathways. Bicifadine is an effective analgesic in 2 models of yeast-induced plantar inflammation (Randall-Selitto and Atkinson-Cowan tests, ED50 ⫽ 9.2, 17.9 mg/kg PO) while showing activity in the tail-flick nociception test. It is also an effective reducing the phenylquinone writhing response (ED50 ⫽ 13 mg/kg PO). In the formalin test, bicifadine significantly decreases the paw licking time in both the early and late phases (MED ⫽ 10 mg/kg PO). Repeated (5 days) administration of bicifadine (50 mg/kg, PO) did not reduce its analgesic activity in the Randall-Selitto test. There is no evidence of motor activation or stereotypies following acute administration, or the development of dependency following 48 days of bicifadine administration. In conclusion, bicifadine is a potent and effective oral analgesic in a variety of models of acute inflammatory pain and nociception. Moreover, there is no evidence of the development of tolerance or abuse liability associated with bicifadine administration.
S Song; Yeungnam University Hospital, Daegu, South Korea Ketamine, competitive non-NMDA antagonist, is used to treat postoperative and neuropathic pain. However, systemically administered ketamine has some adverse effects such as hallucination and/or hypertension and tachycardia. Some investigators insist that NMDA antagonist is effective when it is administered before rather than after surgical stimuli. This study was performed to compare the analgesic effects of ketamine by the timing and the route of administration in rat formalin test. Fifty rats were divided into five groups; control (saline injected), two systemic (intraperitoneal injection of 0.25 mg/0.1 ml of ketamine 5 min before or after formalin injection; Pre-IP/Post-IP), and two peripheral (subcutaneous infiltration of 0.25 mg/0.1 ml of ketamine on right hind paw in the same site of formalin injection 5 min before or after formalin injection; Pre-LO/Post-LO) groups. Under enflurane anesthesia, all rats were received subcutaneous infiltration of 50 ug of 5% formalin on their right hind paw according to their allocated groups. The number of flinches was compared during 2 (20-60 min0 after formalin injection. All four ketamine groups were significantly less flinches than in control (P ⬍ 0.01). There were no significant differences according to the timing of administration (Pre-IP vs. Post-IP, Pre-LO vs. Post-LO, respectively). Pre-Lo group was significantly less flinches than in two systemic groups (P ⬍ 0.05). These data suggest that subcutaneous infiltration of ketamine has local analgesic effect and the timing of administration is not major factor in its peripheral analgesia.
Abstracts
(665) Cannabinoid agonist WIN55,212-2 suppresses opioidinduced pruritus in mice
(667) Bicifadine is an efficacious analgesic in animal models of neuropathic pain
H Lee, M Ko, S Oh, K Shin; Korea University, College of Medicine, Seoul, Korea Cannabinoid receptor agonists receptor can reversed opioid-induced nausea, vomiting in animals but have not been tested against opioidinduced pruritus yet. This study tests the hypothesis that cannabinoid receptor agonist will prevent opioid-induced pruritus and also tests that cannabinoid receptor agonist will increase the analgesic efficacy of opioids in that dose range. Male ICR mice, 20-25 g, were used. All drugs were injected subcutaneously. For getting the dose-response curve of fentanyl by writhing test, acetic acid (0.6%, 0.4 ml, i.p.) was injected 5 minute prior to 10 minute observation period. Various doses of fentanyl (vehicle, 0.001, 0.0032, 0.01, 0.032, 0.1 mg/kg, 10 ml/kg) were pretreated 15 min earlier. To observe analgesic potentiation of WIN55,212-2 in writhing test, various concentration of WIN55,212-2 (0.25, 0.5, 1.0, 2.0 mg/kg, 10 min PT) were pretreated 10 minutes earlier than the injection of ED50 dose of fentanyl from previous dose-response curve. To observe antipruritogenic effect of WIN55,212-2 in scratching test, various dose of WIN55,212-2 (0.25, 0.5 mg/kg) were pretreated 20 minutes earlier than fentanyl injection. AM251 (3 mg/kg) was used to confirm receptor selectivity. The ED50 of fentanyl in writhing test was 0.018 (0.011-0.025) mg/kg. WIN55,212-2, 1 mg/kg, can increase the analgesic efficacy of fentanyl significantly (p ⬍ 0.01) but not 0.25, 0.5 mg/kg. WIN55,212-5, 0.25 mg/kg can reduce the scratching responses of fentanyl significantly (p ⬍ 0.01) and these were receptor selective. These results demonstrate that WIN55,212-2, 0.25 mg/kg, can prevents opioid-induced pruritus and the antipruritogenic activity of WIN55,212-2 occurs at CB1 receptors even if analgesic efficacy of fentanyl cannot be increased in that dose.
A Basile, E Koustova, A Lippa, P Skolnick; DOV Pharmaceutical, Inc, Hackensack, NJ Bicifadine (DOV 220,075), a balanced inhibitor of norepinephrine and serotonin uptake, was evaluated in two models of neuropathic pain: streptozotocin-induced diabetic neuropathy, and the spinal nerve ligation (SNL) model (Kim and Chung, 1992). In the diabetic neuropathy model, the effect of bicifadine on the paw pressure withdrawal threshold was determined using the Randall-Selitto test. Bicifadine’s efficacy in reducing mechanical allodynia in the SNL model was measured using Semmes-Weinstein filaments and its effects on mechanical and thermal hyperalgesia were evaluated with the Randall-Selitto test and a focused beam of infrared radiation, respectively. Bicifadine dose-dependently reduced the nociceptive threshold for paw withdrawal in diabetic rats (ED50 ⫽ 5 mg/kg PO). Similarly, bicifadine reduced mechanical allodynia in the SNL model, with a maximum anti-allodynic action observed at 40mg/kg PO, an effect comparable in magnitude to 300 mg/kg PO of gabapentin. In addition, bicifadine induced anti-mechanical (ED50 ⫽ 12 mg/kg PO) and thermal (MED 12.5 mg/kg PO) hyperalgesic effects. The effect of bicifadine in blocking mechanical hyperalgesia in the SNL model reached a maximum at 60 minutes and remained significant up to 120 minutes after administration. Its effects in blocking thermal hyperalgesia reached a maximum at 30 minutes and lasted up to 240 minutes after administration. Chronic administration (50mg/kg/day, 5 days, PO) of bicifadine did not result in the development of analgesic tolerance, with efficacy in reducing mechanical hyperalgesia in SNL rats similar to acute bicifadine (50mg/kg). In contrast, repeated administration of morphine (128 mg/kg/D, 5 days, PO) resulted in a significant reduction in efficacy. In conclusion, bicifadine is a potent and efficacious analgesic in two well-described models of neuropathic pain, and exhibits no abuse potential.
(666) Bicifadine: Characterization of its molecular pharmacology and efficacy in animal models of acute pain
(668) Peripheral analgesic effect of ketamine
E Koustova, A Basile, A Lippa, P Skolnick; DOV Pharmaceutical, Inc, Hackensack, NJ Bicifadine (DOV 220,075) is a balanced inhibitor of norepinephrine and serotonin uptake (IC50 ⫽ 55⫾3, 117⫾26 nM, respectively) which exhibits no significant affinity for , , and ␦ opioid receptor subtypes as well as a host of other receptors/ion channels/enzymes, including the NMDA, nicotinic and muscarinic cholinergic, vanilloid, orphanin, NK and cannabinoid receptors, voltage-gated sodium, potassium and N-type calcium channels, and COX1, COX2. This profile suggests that the primary molecular mechanism responsible for analgesic actions of bicifadine relates to its ability to modulate monoaminergic neurotransmitter pathways. Bicifadine is an effective analgesic in 2 models of yeast-induced plantar inflammation (Randall-Selitto and Atkinson-Cowan tests, ED50 ⫽ 9.2, 17.9 mg/kg PO) while showing activity in the tail-flick nociception test. It is also an effective reducing the phenylquinone writhing response (ED50 ⫽ 13 mg/kg PO). In the formalin test, bicifadine significantly decreases the paw licking time in both the early and late phases (MED ⫽ 10 mg/kg PO). Repeated (5 days) administration of bicifadine (50 mg/kg, PO) did not reduce its analgesic activity in the Randall-Selitto test. There is no evidence of motor activation or stereotypies following acute administration, or the development of dependency following 48 days of bicifadine administration. In conclusion, bicifadine is a potent and effective oral analgesic in a variety of models of acute inflammatory pain and nociception. Moreover, there is no evidence of the development of tolerance or abuse liability associated with bicifadine administration.
S Song; Yeungnam University Hospital, Daegu, South Korea Ketamine, competitive non-NMDA antagonist, is used to treat postoperative and neuropathic pain. However, systemically administered ketamine has some adverse effects such as hallucination and/or hypertension and tachycardia. Some investigators insist that NMDA antagonist is effective when it is administered before rather than after surgical stimuli. This study was performed to compare the analgesic effects of ketamine by the timing and the route of administration in rat formalin test. Fifty rats were divided into five groups; control (saline injected), two systemic (intraperitoneal injection of 0.25 mg/0.1 ml of ketamine 5 min before or after formalin injection; Pre-IP/Post-IP), and two peripheral (subcutaneous infiltration of 0.25 mg/0.1 ml of ketamine on right hind paw in the same site of formalin injection 5 min before or after formalin injection; Pre-LO/Post-LO) groups. Under enflurane anesthesia, all rats were received subcutaneous infiltration of 50 ug of 5% formalin on their right hind paw according to their allocated groups. The number of flinches was compared during 2 (20-60 min0 after formalin injection. All four ketamine groups were significantly less flinches than in control (P ⬍ 0.01). There were no significant differences according to the timing of administration (Pre-IP vs. Post-IP, Pre-LO vs. Post-LO, respectively). Pre-Lo group was significantly less flinches than in two systemic groups (P ⬍ 0.05). These data suggest that subcutaneous infiltration of ketamine has local analgesic effect and the timing of administration is not major factor in its peripheral analgesia.