Methods and Findings in Experimental and Clinical Pharmacology, 2008
with nerve injury in rats (9-11) and humans (12-15). Thus, it is likely that low doses of anticon... more with nerve injury in rats (9-11) and humans (12-15). Thus, it is likely that low doses of anticonvulsants and B vitamins might have synergistic effects in reducing neuropathic pain and side effects.
Resveratrol is a phytoalexin structurally related to stilbenes, which is synthesized in considera... more Resveratrol is a phytoalexin structurally related to stilbenes, which is synthesized in considerable amounts in the skin of grapes, raspberries, mulberries, pistachios and peanuts, and by at least 72 medicinal and edible plant species in response to stress conditions. It was isolated in 1940 and did not maintain much interest for around five decades until its role in treatment of cardiovascular diseases was suggested. To date, resveratrol has been identified as an agent that may be useful to treat cancer, pain, inflammation, tissue injury, and other diseases. However, currently the attention is being focused in analyzing its properties against neurodegenerative diseases and as antiaging compound. It has been reported that resveratrol shows effects in in vitro models of epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and nerve injury. However, evidences in vivo as well as in human beings are still lacking. Thus, further investigations on the pharmacological effects of resveratrol in vivo are necessary before any conclusions on its effects on neurodegenerative diseases can be obtained.
The purpose of this study was to investigate the possible antinociceptive effect of Heterotheca i... more The purpose of this study was to investigate the possible antinociceptive effect of Heterotheca inuloides in inflammatory pain and to identify the main compounds involved in this effect. Dose-response curves were obtained for hexane, dichlorometane, ethyl acetate and methanol extracts from Heterotheca inuloides inflorescences in the formalin test. Hexane extract was more potent and effective than other extracts. Bio-guided fractionation was performed to determine the main antinociceptive compounds of the plant. Gas chromatography-mass spectrometry technique demonstrated the composition of the most active fraction from hexane extract revealing the presence of caryophyllene oxide, cedrene, 7-hydroxy-3,4-dihydrocadalin, 7-hydroxycadalene and a compound not identified. The isolated compounds were individually evaluated in the formalin test in a preliminary dose of 100 μg/paw and only 7-hydroxy-3,4-dihydrocadalin showed a significant antinociceptive effect. Dose-response curves were then obtained for 7-hydroxy-3,4-dihydrocadalin and diclofenac, a prototypical analgesic drug. Both drugs were equieffective and equipotent in the second phase of the formalin test, but 7-hydroxy-3,4-dihydrocadalin was more effective and potent in the first phase than diclofenac. In addition, 7-hydroxy-3,4-dihydrocadalin reduced carrageenan-induced mechanical hyperalgesia and inflammation in a dose-dependent manner. Finally, in mechanistic studies, the antinociceptive effect of 7-hydroxy-3,4-dihydrocadalin in the formalin test was prevented by methiothepin, WAY100635, SB224289 and BRL15572 but not by naltrexone. Results support the use of H. inuloides inflorescences as analgesic in the Mexican traditional medicine. Moreover, data indicate that 7-hydroxy-3,4-dihydrocadalin is partly responsible of this pharmacological activity, and suggest that 5-HT(1A), 5-HT(1B), and 5-HT(1D) serotonergic, but not opioid, receptors participate in the antinociceptive effect of this drug.
... 91 Synergistic Interaction between Spinal Gabapentin and Oral B Vitamins in a Neuropathic Pai... more ... 91 Synergistic Interaction between Spinal Gabapentin and Oral B Vitamins in a Neuropathic Pain Model Gerardo Reyes-García1, Roberto Medina-Santillán1, Héctor I. Rocha-González2 and Vinicio Granados-Soto2,3* ... 27. Yaksh TL and Rudy TA: Physiol Behav 17: 1031 (1976). ...
This work analyzes the role of cholecystokinin (CCK) receptors, dynorphin A 1-17 and descending f... more This work analyzes the role of cholecystokinin (CCK) receptors, dynorphin A 1-17 and descending facilitation originated in the rostral ventromedial medulla (RVM) on secondary allodynia and hyperalgesia in formalininjected rats. Formalin injection (50 μL, 1%, s.c.) produced acute nociception (lasting 1 h) and long-term secondary allodynia and hyperalgesia in ipsilateral and contralateral hind paws (lasting 1-12 days). Once established, intra-RVM administration of lidocaine at day 6, but not at 2, reversed secondary allodynia and hyperalgesia in rats. The injection of YM022 (CCK 2 receptor antagonist), but not lorglumide (CCK 1 receptor antagonist), into the RVM or spinal cord reversed both nociceptive behaviors. Pre-treatment with lidocaine, lorglumide or YM022 did not prevent the development of secondary allodynia or hyperalgesia regardless of the administration route. Formalin injection increased dynorphin content in the dorsal, but not the ventral, spinal cord sections at day 6. Moreover, intrathecal administration of dynorphin antiserum reversed, but was unable to prevent, secondary allodynia and hyperalgesia in both hind paws. These results suggest that formalin-induced secondary allodynia and hyperalgesia are maintained by activation of descending facilitatory mechanisms which are dependent on CCK 2 receptors located in the RVM and spinal cord. In addition, data suggest that spinal dynorphin A 1-17 and CCK play an important role in formalin-induced secondary allodynia and hyperalgesia.
ergism. Data confirm that low doses of the gabapentin and metamizol can interact synergistically ... more ergism. Data confirm that low doses of the gabapentin and metamizol can interact synergistically to reduce formalininduced nociceptive behavior suggesting that this combination could be useful to treat inflammatory pain in humans.
Vitamin B 2 (riboflavin) has been proposed as a prophylactic therapy of migraine. However, so far... more Vitamin B 2 (riboflavin) has been proposed as a prophylactic therapy of migraine. However, so far there are no preclinical studies about the analgesic properties of this vitamin. The current study was designed to investigate the possible antinociceptive, antihyperalgesic and antiallodynic effect of riboflavin in formalin, carrageenan-induced thermal hyperalgesia, and spinal nerve ligation models, respectively. Oral riboflavin produced a dose-related antinociceptive (6.25 -50 mg/kg), antihyperalgesic (25 -150 mg/kg) and anti-inflammatory (50 -150 mg/ kg) effect. Gabapentin (100 mg/kg, positive control), but not riboflavin (150 -600 mg/kg), reduced tactile allodynia in neuropathic rats. Riboflavin-induced antinociception in the formalin test was reversed by pretreatment with N G -L-nitro-arginine methyl ester and glibenclamide, but not by N G -D-nitro-arginine methyl ester or naloxone. Our results indicate that riboflavin is able to produce antinociception and anti-inflammatory, but not antiallodynic, effect in the rat. The effect of riboflavin could be due to the activation of K + channels or nitric oxide release, but not activation of opioid mechanisms. D
The possible antiallodynic effect of phosphodiesterase 5 inhibitor sildenafil and nitric oxide do... more The possible antiallodynic effect of phosphodiesterase 5 inhibitor sildenafil and nitric oxide donor glyceryl trinitrate as well as the changes in phosphodiesterase 5A2 mRNA expression in dorsal root ganglion and spinal cord of allodynic diabetic rats was assessed. Diabetes was induced by streptozotocin (50 mg/kg, i.p.) in male Wistar rats. Streptozotocin injection produced hyperlglycemia, polydipsia, polyphagia and polyuria as well as long-term tactile allodynia (12 weeks) and a reduction of phosphodiesterase 5A2 mRNA expression in spinal cord of diabetic rats. Systemic administration of sildenafil (1-5.6 mg/kg, i.p.) reduced tactile allodynia in a dose-dependent manner in diabetic rats. Likewise, glyceryl trinitrate patches (0.2 mg/h) also reduced tactile allodynia in diabetic rats. Moreover, both drugs reversed streptozotocin-induced phosphodiesterase 5A2 mRNA expression reduction. Our results indicate that glyceryl trinitrate and sildenafil reduce tactile allodynia in diabetic rats suggesting that nitric oxide and cyclic GMP supply is an important step in their mechanism of action of these drugs in diabetic animals. Data suggest that nitric oxide donors (as glyceryl trinitrate) and drugs which increase cyclic GMP levels (as sildenafil) could have a role in the pharmacotherapy of tactile allodynia in diabetic patients.
The possible pronociceptive role of peripheral and spinal 5-HT 7 receptors in the formalin test w... more The possible pronociceptive role of peripheral and spinal 5-HT 7 receptors in the formalin test was assessed. Local administration of 5-HT 7 (SB-269970, 2.5-77.1 nmol/paw), but not 5-HT 1A (WAY-100635, 1-60 nmol/paw), receptor antagonist significantly reduced formalininduced flinching. Local 5-hydroxytryptamine (5-HT, 3-100 nmol/paw) or 5-carboxamidotryptamine (5-CT, 0.3-3 nmol/paw) (a 5-HT 7/1A receptor agonist) augmented, in a dose-dependent manner, 0.5% formalin-induced nociceptive behavior. The local pronociceptive effect of 5-HT or 5-CT was significantly reduced by SB-269970 (25 and 77.1 nmol/paw), but not by WAY-100635 (10 nmol/paw). 5-HT 7 receptors were observed in myelinated and unmyelinated axons of the digital nerves in rat hindpaw. Intrathecal SB-269970 (2.5-77.1 nmol/rat) or WAY-100635 (1-50 nmol/rat) did not modify 1% formalin-induced nociceptive behavior. Spinal 5-HT (25-200 nmol/rat) significantly reduced formalin-induced flinching behavior during phase 2. At lower doses (0.1-3 nmol/rat) intrathecal 5-CT dose-dependently increased flinching during phase 2. In contrast, higher doses (10-30 nmol/rat) of 5-CT reduced formalin-induced nociceptive behavior during both phases. The spinal pronociceptive effect of 5-CT was reduced by SB-269970 (7.7-77 nmol/rat), but not by WAY-100635 (10 nmol/rat). In addition, the spinal antinociceptive effect of 5-CT was partially reversed by WAY-100635 (10 nmol/rat). The spinal antinociceptive effect of 5-HT was unaffected either by SB-269970 (77 nmol/rat) or WAY-100635 (10 nmol/rat). Data suggest that 5-HT 7 , but not 5-HT 1A , receptors play a pronociceptive role in peripheral and spinal sites in the rat formalin test. q
The purpose of this study was to assess the antinociceptive and antiallodynic effect of melatonin... more The purpose of this study was to assess the antinociceptive and antiallodynic effect of melatonin as well as its possible mechanism of action in diabetic rats. Streptozotocin (50 mg/kg) injection caused hyperglycemia within 1 week. Formalin-evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Oral administration of melatonin (10-300 mg/kg) dose-dependently reduced flinching behavior in diabetic rats. In addition, K-185 (a melatonin MT 2 receptor antagonist, 0.2-2 mg/kg, s.c.) completely blocked the melatonin-induced antinociception in diabetic rats, whereas that naltrexone (a non-selective opioid receptor antagonist, 1 mg/kg, s.c.) and naltrindole (a selective δ opioid receptor antagonist, 0.5 mg/kg, s.c.), but not 5′-guanidinonaltrindole (a selective κ opioid receptor antagonist, 1 mg/kg, s.c.), partially reduced the antinociceptive effect of melatonin. Given alone K-185, naltrexone, naltrindole or 5′-guanidinonaltrindole did not modify formalin-induced nociception in diabetic rats. Four to 8 weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. On this condition, oral administration of melatonin (75-300 mg/kg) dose-dependently reduced tactile allodynia in diabetic rats. Both antinociceptive and antiallodynic effects were not related to motor changes as melatonin did not modify number of falls in the rotarod test. Results indicate that melatonin is able to reduce formalin-induced nociception and tactile allodynia in streptozotocin-injected rats. In addition, data suggest that melatonin MT 2 and δ opioid receptors may play an important role in these effects.
Methods and Findings in Experimental and Clinical Pharmacology, 2008
with nerve injury in rats (9-11) and humans (12-15). Thus, it is likely that low doses of anticon... more with nerve injury in rats (9-11) and humans (12-15). Thus, it is likely that low doses of anticonvulsants and B vitamins might have synergistic effects in reducing neuropathic pain and side effects.
Resveratrol is a phytoalexin structurally related to stilbenes, which is synthesized in considera... more Resveratrol is a phytoalexin structurally related to stilbenes, which is synthesized in considerable amounts in the skin of grapes, raspberries, mulberries, pistachios and peanuts, and by at least 72 medicinal and edible plant species in response to stress conditions. It was isolated in 1940 and did not maintain much interest for around five decades until its role in treatment of cardiovascular diseases was suggested. To date, resveratrol has been identified as an agent that may be useful to treat cancer, pain, inflammation, tissue injury, and other diseases. However, currently the attention is being focused in analyzing its properties against neurodegenerative diseases and as antiaging compound. It has been reported that resveratrol shows effects in in vitro models of epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and nerve injury. However, evidences in vivo as well as in human beings are still lacking. Thus, further investigations on the pharmacological effects of resveratrol in vivo are necessary before any conclusions on its effects on neurodegenerative diseases can be obtained.
The purpose of this study was to investigate the possible antinociceptive effect of Heterotheca i... more The purpose of this study was to investigate the possible antinociceptive effect of Heterotheca inuloides in inflammatory pain and to identify the main compounds involved in this effect. Dose-response curves were obtained for hexane, dichlorometane, ethyl acetate and methanol extracts from Heterotheca inuloides inflorescences in the formalin test. Hexane extract was more potent and effective than other extracts. Bio-guided fractionation was performed to determine the main antinociceptive compounds of the plant. Gas chromatography-mass spectrometry technique demonstrated the composition of the most active fraction from hexane extract revealing the presence of caryophyllene oxide, cedrene, 7-hydroxy-3,4-dihydrocadalin, 7-hydroxycadalene and a compound not identified. The isolated compounds were individually evaluated in the formalin test in a preliminary dose of 100 μg/paw and only 7-hydroxy-3,4-dihydrocadalin showed a significant antinociceptive effect. Dose-response curves were then obtained for 7-hydroxy-3,4-dihydrocadalin and diclofenac, a prototypical analgesic drug. Both drugs were equieffective and equipotent in the second phase of the formalin test, but 7-hydroxy-3,4-dihydrocadalin was more effective and potent in the first phase than diclofenac. In addition, 7-hydroxy-3,4-dihydrocadalin reduced carrageenan-induced mechanical hyperalgesia and inflammation in a dose-dependent manner. Finally, in mechanistic studies, the antinociceptive effect of 7-hydroxy-3,4-dihydrocadalin in the formalin test was prevented by methiothepin, WAY100635, SB224289 and BRL15572 but not by naltrexone. Results support the use of H. inuloides inflorescences as analgesic in the Mexican traditional medicine. Moreover, data indicate that 7-hydroxy-3,4-dihydrocadalin is partly responsible of this pharmacological activity, and suggest that 5-HT(1A), 5-HT(1B), and 5-HT(1D) serotonergic, but not opioid, receptors participate in the antinociceptive effect of this drug.
... 91 Synergistic Interaction between Spinal Gabapentin and Oral B Vitamins in a Neuropathic Pai... more ... 91 Synergistic Interaction between Spinal Gabapentin and Oral B Vitamins in a Neuropathic Pain Model Gerardo Reyes-García1, Roberto Medina-Santillán1, Héctor I. Rocha-González2 and Vinicio Granados-Soto2,3* ... 27. Yaksh TL and Rudy TA: Physiol Behav 17: 1031 (1976). ...
This work analyzes the role of cholecystokinin (CCK) receptors, dynorphin A 1-17 and descending f... more This work analyzes the role of cholecystokinin (CCK) receptors, dynorphin A 1-17 and descending facilitation originated in the rostral ventromedial medulla (RVM) on secondary allodynia and hyperalgesia in formalininjected rats. Formalin injection (50 μL, 1%, s.c.) produced acute nociception (lasting 1 h) and long-term secondary allodynia and hyperalgesia in ipsilateral and contralateral hind paws (lasting 1-12 days). Once established, intra-RVM administration of lidocaine at day 6, but not at 2, reversed secondary allodynia and hyperalgesia in rats. The injection of YM022 (CCK 2 receptor antagonist), but not lorglumide (CCK 1 receptor antagonist), into the RVM or spinal cord reversed both nociceptive behaviors. Pre-treatment with lidocaine, lorglumide or YM022 did not prevent the development of secondary allodynia or hyperalgesia regardless of the administration route. Formalin injection increased dynorphin content in the dorsal, but not the ventral, spinal cord sections at day 6. Moreover, intrathecal administration of dynorphin antiserum reversed, but was unable to prevent, secondary allodynia and hyperalgesia in both hind paws. These results suggest that formalin-induced secondary allodynia and hyperalgesia are maintained by activation of descending facilitatory mechanisms which are dependent on CCK 2 receptors located in the RVM and spinal cord. In addition, data suggest that spinal dynorphin A 1-17 and CCK play an important role in formalin-induced secondary allodynia and hyperalgesia.
ergism. Data confirm that low doses of the gabapentin and metamizol can interact synergistically ... more ergism. Data confirm that low doses of the gabapentin and metamizol can interact synergistically to reduce formalininduced nociceptive behavior suggesting that this combination could be useful to treat inflammatory pain in humans.
Vitamin B 2 (riboflavin) has been proposed as a prophylactic therapy of migraine. However, so far... more Vitamin B 2 (riboflavin) has been proposed as a prophylactic therapy of migraine. However, so far there are no preclinical studies about the analgesic properties of this vitamin. The current study was designed to investigate the possible antinociceptive, antihyperalgesic and antiallodynic effect of riboflavin in formalin, carrageenan-induced thermal hyperalgesia, and spinal nerve ligation models, respectively. Oral riboflavin produced a dose-related antinociceptive (6.25 -50 mg/kg), antihyperalgesic (25 -150 mg/kg) and anti-inflammatory (50 -150 mg/ kg) effect. Gabapentin (100 mg/kg, positive control), but not riboflavin (150 -600 mg/kg), reduced tactile allodynia in neuropathic rats. Riboflavin-induced antinociception in the formalin test was reversed by pretreatment with N G -L-nitro-arginine methyl ester and glibenclamide, but not by N G -D-nitro-arginine methyl ester or naloxone. Our results indicate that riboflavin is able to produce antinociception and anti-inflammatory, but not antiallodynic, effect in the rat. The effect of riboflavin could be due to the activation of K + channels or nitric oxide release, but not activation of opioid mechanisms. D
The possible antiallodynic effect of phosphodiesterase 5 inhibitor sildenafil and nitric oxide do... more The possible antiallodynic effect of phosphodiesterase 5 inhibitor sildenafil and nitric oxide donor glyceryl trinitrate as well as the changes in phosphodiesterase 5A2 mRNA expression in dorsal root ganglion and spinal cord of allodynic diabetic rats was assessed. Diabetes was induced by streptozotocin (50 mg/kg, i.p.) in male Wistar rats. Streptozotocin injection produced hyperlglycemia, polydipsia, polyphagia and polyuria as well as long-term tactile allodynia (12 weeks) and a reduction of phosphodiesterase 5A2 mRNA expression in spinal cord of diabetic rats. Systemic administration of sildenafil (1-5.6 mg/kg, i.p.) reduced tactile allodynia in a dose-dependent manner in diabetic rats. Likewise, glyceryl trinitrate patches (0.2 mg/h) also reduced tactile allodynia in diabetic rats. Moreover, both drugs reversed streptozotocin-induced phosphodiesterase 5A2 mRNA expression reduction. Our results indicate that glyceryl trinitrate and sildenafil reduce tactile allodynia in diabetic rats suggesting that nitric oxide and cyclic GMP supply is an important step in their mechanism of action of these drugs in diabetic animals. Data suggest that nitric oxide donors (as glyceryl trinitrate) and drugs which increase cyclic GMP levels (as sildenafil) could have a role in the pharmacotherapy of tactile allodynia in diabetic patients.
The possible pronociceptive role of peripheral and spinal 5-HT 7 receptors in the formalin test w... more The possible pronociceptive role of peripheral and spinal 5-HT 7 receptors in the formalin test was assessed. Local administration of 5-HT 7 (SB-269970, 2.5-77.1 nmol/paw), but not 5-HT 1A (WAY-100635, 1-60 nmol/paw), receptor antagonist significantly reduced formalininduced flinching. Local 5-hydroxytryptamine (5-HT, 3-100 nmol/paw) or 5-carboxamidotryptamine (5-CT, 0.3-3 nmol/paw) (a 5-HT 7/1A receptor agonist) augmented, in a dose-dependent manner, 0.5% formalin-induced nociceptive behavior. The local pronociceptive effect of 5-HT or 5-CT was significantly reduced by SB-269970 (25 and 77.1 nmol/paw), but not by WAY-100635 (10 nmol/paw). 5-HT 7 receptors were observed in myelinated and unmyelinated axons of the digital nerves in rat hindpaw. Intrathecal SB-269970 (2.5-77.1 nmol/rat) or WAY-100635 (1-50 nmol/rat) did not modify 1% formalin-induced nociceptive behavior. Spinal 5-HT (25-200 nmol/rat) significantly reduced formalin-induced flinching behavior during phase 2. At lower doses (0.1-3 nmol/rat) intrathecal 5-CT dose-dependently increased flinching during phase 2. In contrast, higher doses (10-30 nmol/rat) of 5-CT reduced formalin-induced nociceptive behavior during both phases. The spinal pronociceptive effect of 5-CT was reduced by SB-269970 (7.7-77 nmol/rat), but not by WAY-100635 (10 nmol/rat). In addition, the spinal antinociceptive effect of 5-CT was partially reversed by WAY-100635 (10 nmol/rat). The spinal antinociceptive effect of 5-HT was unaffected either by SB-269970 (77 nmol/rat) or WAY-100635 (10 nmol/rat). Data suggest that 5-HT 7 , but not 5-HT 1A , receptors play a pronociceptive role in peripheral and spinal sites in the rat formalin test. q
The purpose of this study was to assess the antinociceptive and antiallodynic effect of melatonin... more The purpose of this study was to assess the antinociceptive and antiallodynic effect of melatonin as well as its possible mechanism of action in diabetic rats. Streptozotocin (50 mg/kg) injection caused hyperglycemia within 1 week. Formalin-evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Oral administration of melatonin (10-300 mg/kg) dose-dependently reduced flinching behavior in diabetic rats. In addition, K-185 (a melatonin MT 2 receptor antagonist, 0.2-2 mg/kg, s.c.) completely blocked the melatonin-induced antinociception in diabetic rats, whereas that naltrexone (a non-selective opioid receptor antagonist, 1 mg/kg, s.c.) and naltrindole (a selective δ opioid receptor antagonist, 0.5 mg/kg, s.c.), but not 5′-guanidinonaltrindole (a selective κ opioid receptor antagonist, 1 mg/kg, s.c.), partially reduced the antinociceptive effect of melatonin. Given alone K-185, naltrexone, naltrindole or 5′-guanidinonaltrindole did not modify formalin-induced nociception in diabetic rats. Four to 8 weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. On this condition, oral administration of melatonin (75-300 mg/kg) dose-dependently reduced tactile allodynia in diabetic rats. Both antinociceptive and antiallodynic effects were not related to motor changes as melatonin did not modify number of falls in the rotarod test. Results indicate that melatonin is able to reduce formalin-induced nociception and tactile allodynia in streptozotocin-injected rats. In addition, data suggest that melatonin MT 2 and δ opioid receptors may play an important role in these effects.
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