Suppression of TLR4/MyD88/TAK1/NF-κB/COX-2 Signaling Pathway in the Central Nervous System by Bexarotene,a Selective RXR Agonist,Prevents Hyperalgesia in the Lipopolysaccharide-Induced Pain Mouse Model

Neurochemical Research - A selective RXR agonist, bexarotene, has been shown to have anti-inflammatory, anti-nociceptive, and neuroprotective effects in several models of numerous neurological...     

Biological Time‐Dependent Difference in Effect of Peroxynitrite Demonstrated by the Mouse Hot Plate Pain Model

We previously demonstrated the rhythmic pattern of L‐arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) cascade in nociceptive processes. The coupled production of excess NO and superoxide leads to the formation of an unstable intermediate peroxynitrite, which is primarily responsible for NO‐mediated toxicity. In the present study, we evaluated the biological time‐dependent effects of exogenously administered peroxynitrite on nociceptive processes and peroxynitrite‐induced changes in the analgesic effect of morphine using the mouse hot‐plate pain model. Experiments were performed at four different times of day (1, 7, 13, and 19 hours after lights on, i.e., HALO) in mice of both sexes synchronized to a 12 h:12 h light‐dark cycle. Animals were injected intraperitoneally (i.p.) with saline or 10 mg/kg morphine 30 min before and 0.001 mg/kg peroxynitrite 30 sec before hot‐plate testing, respectively. The analgesic effect of morphine exhibited significant biological time‐dependent differences in the thermally‐induced algesia; whereas, administration of peroxynitrite alone exhibited either significant algesic or analgesic effect, depending on the circadian time of its injection. Concomitant administration of peroxynitrite and morphine reduced morphine‐induced analgesia at three of the four different study time points. In conclusion, peroxynitrite displayed nociceptive and antinociceptive when administered alone according to the circadian time of treatment, while it diminished analgesic activity when administered in combination with morphine at certain biological times.     

Biological time-dependent difference in effect of peroxynitrite demonstrated by the mouse hot plate pain model

We previously demonstrated the rhythmic pattern of L-arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) cascade in nociceptive processes. The coupled production of excess NO and superoxide leads to the formation of an unstable intermediate peroxynitrite, which is primarily responsible for NO-mediated toxicity. In the present study, we evaluated the biological time-dependent effects of exogenously administered peroxynitrite on nociceptive processes and peroxynitrite-induced changes in the analgesic effect of morphine using the mouse hot-plate pain model. Experiments were performed at four different times of day (1, 7, 13, and 19 hours after lights on, i.e., HALO) in mice of both sexes synchronized to a 12 h:12 h light-dark cycle. Animals were injected intraperitoneally (i.p.) with saline or 10 mg/kg morphine 30 min before and 0.001 mg/kg peroxynitrite 30 sec before hot-plate testing, respectively. The analgesic effect of morphine exhibited significant biological time-dependent differences in the thermally-induced algesia; whereas, administration of peroxynitrite alone exhibited either significant algesic or analgesic effect, depending on the circadian time of its injection. Concomitant administration of peroxynitrite and morphine reduced morphine-induced analgesia at three of the four different study time points. In conclusion, peroxynitrite displayed nociceptive and antinociceptive when administered alone according to the circadian time of treatment, while it diminished analgesic activity when administered in combination with morphine at certain biological times.     

Inhibition by nitric oxide of cytochrome P450 4A activity contributes to endotoxin-induced hypotension in rats.

Nitric oxide (NO) production during endotoxemia is associated with decreased total CYP content, CYP 1A1/2, 2B1/2, 2C6, 2C11, 3A1, and 3A2 mRNA, protein expression or activity which is prevented by NO synthase (NOS) inhibitors in rats. This study was conducted to determine if endotoxin-induced hypotension caused by NO production is mediated by inhibition of renal CYP 4A protein expression and activity. In conscious male Sprague-Dawley rats, endotoxin (10 mg/kg, ip) reduced mean arterial pressure (MAP), increased serum and renal nitrite levels, and inducible NOS (iNOS), and decreased renal CYP 4A1/A3 protein and CYP 4A activity. The selective iNOS inhibitor 1,3-PBIT (10 mg/kg, ip; 1h after endotoxin) prevented endotoxin-induced decrease in MAP, renal CYP 4A1/A3 protein level and CYP 4A activity and increase in systemic and renal nitrite production. The selective constitutive NOS (cNOS) inhibitor N(G)-nitro-L-arginine (L-NNA; 20 mg/kg, ip; 1 h after endotoxin) partially attenuated endotoxin-induced decrease in MAP. The selective CYP 4A inhibitor, aminobenzotriazole (50 mg/kg, ip; 1 h after endotoxin) diminished CYP 4A1/A3 protein level and CYP 4A activity. Aminobenzotriazole did not alter the endotoxin-induced decrease in MAP, but it reversed the effect of 1,3-PBIT in preventing endotoxin-induced fall in MAP and CYP 4A activity. These data suggest that the endotoxemia-induced increase in NO production primarily via iNOS suppresses renal CYP 4A expression and activity, and inhibition of iNOS with 1,3-PBIT restores renal CYP 4A protein and activity and MAP presumably due to increased production of arachidonic acid metabolites derived from CYP 4A.     

Twenty‐Four‐Hour Variation of L‐Arginine/Nitric Oxide/Cyclic Guanosine Monophosphate Pathway Demonstrated by the Mouse Visceral Pain Model

The L‐arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway is known to be involved in central and peripheral nociceptive processes. This study evaluated the rhythmic pattern of the L‐arginine/NO/cGMP pathway using the mouse visceral pain model. Experiments were performed at six different times (1, 5, 9, 13, 17, and 21 h after light on) per day in male mice synchronized to a 12 h:12 h light‐dark cycle. Animals were injected s.c. with saline, 2 mg/kg L‐arginine (a NO precursor), 75 mg/kg L‐N^G‐nitroarginine methyl ester (L‐NAME, a NOS inhibitor), 40 mg/kg methylene blue (a soluble guanylyl cyclase and/or NOS inhibitor), or 0.1 mg/kg sodium nitroprusside (a nonenzymatic NO donor) 15 min before counting 2.5 mg/kg (i.p.) p‐benzoquinone (PBQ)‐induced abdominal constrictions for 15 min. Blood samples were collected after the test, and the nitrite concentration was determined in serum samples. L‐arginine or L‐NAME caused both antinociception and nociception, depending on the circadian time of their injection. The analgesic effect of methylene blue or sodium nitroprusside exhibited significant biological time‐dependent differences in PBQ‐induced abdominal constrictions. Serum nitrite levels also displayed a significant 24 h variation in mice injected with PBQ, L‐NAME, methylene blue, or sodium nitroprusside, but not saline or L‐arginine. These results suggest that components of L‐arginine/NO/cGMP pathway exhibit biological time‐dependent effects on visceral nociceptive process.     

Twenty-four-hour variation of L-arginine/nitric oxide/cyclic guanosine monophosphate pathway demonstrated by the mouse visceral pain model

The L-arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway is known to be involved in central and peripheral nociceptive processes. This study evaluated the rhythmic pattern of the L-arginine/NO/cGMP pathway using the mouse visceral pain model. Experiments were performed at six different times (1, 5, 9, 13, 17, and 21 h after light on) per day in male mice synchronized to a 12 h:12 h light-dark cycle. Animals were injected s.c. with saline, 2 mg/kg L-arginine (a NO precursor), 75 mg/kg L-N(G)-nitroarginine methyl ester (L-NAME, a NOS inhibitor), 40 mg/kg methylene blue (a soluble guanylyl cyclase and/or NOS inhibitor), or 0.1 mg/kg sodium nitroprusside (a nonenzymatic NO donor) 15 min before counting 2.5 mg/kg (i.p.) p-benzoquinone (PBQ)-induced abdominal constrictions for 15 min. Blood samples were collected after the test, and the nitrite concentration was determined in serum samples. L-arginine or L-NAME caused both antinociception and nociception, depending on the circadian time of their injection. The analgesic effect of methylene blue or sodium nitroprusside exhibited significant biological time-dependent differences in PBQ-induced abdominal constrictions. Serum nitrite levels also displayed a significant 24 h variation in mice injected with PBQ, L-NAME, methylene blue, or sodium nitroprusside, but not saline or L-arginine. These results suggest that components of L-arginine/NO/cGMP pathway exhibit biological time-dependent effects on visceral nociceptive process.