title: Effects of selective and non-selective inhibitors of nitric oxide synthase on morphine- and endomorphin-1-induced analgesia in acute and neuropathic pain in rats.
abstract: Nitric oxide (NO) has been reported to be involved in the mechanisms of pain generation throughout the nervous system. We examined the effects of intrathecally (i.t.) administered nitric oxide synthase (NOS) inhibitors on the antinociceptive effects of morphine and endomorphin-1 during acute pain and in chronic constriction injury (CCI)-exposed rats. We used N(G)-nitro-l-arginine methyl ester (l-NAME), a non-selective NOS inhibitor; 7-nitroindazole (7-NI) or 1-(2-trifluoromethyl-phenyl)-imidazole (TRIM), selective inhibitors of neuronal NOS (NOS1); and 1400W dihydrochloride, a selective inhibitor of inducible NOS (NOS2). Morphine (0.5-2.5 μg) and endomorphin-1 (2.5-20 μg) in acute pain and morphine (10-40 μg) and endomorphin-1 (5-20 μg) after CCI-injury were combined with NOS inhibitors. For acute pain, the ED50 for endomorphin-1 (7.1 μg) was higher than that of morphine (1.3 μg) in the tail-flick test. For neuropathic pain, the ED50 value for morphine was much higher (43.2 μg) than that of endomorphin-1 (9.2 μg) in von Frey test. NOS inhibitors slightly influenced pain thresholds in both pain models. Moreover, in neuropathic pain, the effects of morphine were more potentiated by L-NAME, TRIM, 7-NI and 1400W (12×, 8.6×, 4.1× and 5.3×, respectively) than were the effects of endomorphin-1 (2.7×, 4.3×, 3.4× and 2.1×, respectively) in the von Frey test. Minocycline which is known to enhance the efficiency of morphine in neuropathic pain, decreased the mRNA expression of NOS1 in the DRG and NOS2 and C1q in the spinal cord after CCI. Both NOS2 and IBA-1 protein levels in the spinal cord and NOS1, NOS2 and IBA1 protein levels in DRG decreased after minocycline administration. In conclusion, our results provide evidence that both neuronal and non-neuronal NOS/NO pathways contribute to the behavioural pain responses evoked by nerve injury. The NOS inhibitors regardless of the type of pain enhanced morphine antinociception and, to a lesser extent, altered the effects of endomorphin-1, an opioid ligand with a peptidergic structure.
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
authors.forename: Wioletta
authors.initials: W
authors.lastname: Makuch
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Mika
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Rojewska
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zychowska
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland. Electronic address: przebar@if-pan.krakow.pl.
authors.forename: Barbara
authors.initials: B
authors.lastname: Przewlocka
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009020:Morphine / Q000627:therapeutic use*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000187:drug effects*; D010147:Pain Measurement; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism; D012585:Sciatica / Q000188:drug therapy* / Q000473:pathology; D013116:Spinal Cord / Q000201:enzymology; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D007191:Indazoles; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D012333:RNA, Messenger; D011951:Receptors, Complement; C032402:complement 1q receptor; C105293:endomorphin 1; D009020:Morphine; D019001:Nitric Oxide Synthase; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester
keywords: % MPE; 1-(2-Trifluoromethyl-phenyl)-imidazole; 1400W; 7-NI; 7-Nitroindazole; CCI; DRG; EM-1; M; Mechanical allodynia; N-([3-(Aminomethyl)phenyl]methyl)ethanimidamide dihydrochloride (1400W dihydrochloride); NG-nitro-l-arginine methyl ester; NO; NOS; Neuropathic pain; Nitric oxide; Nitric oxide synthase; Nociception; TRIM; Thermal hyperalgesia; cGMP; chronic constriction injury; cyclic guanosine monophosphate; dorsal root ganglia; endomorphin-1; i.t.; intrathecal; l-NAME; morphine; nitric oxide; nitric oxide synthase; percentage of maximal possible antinociceptive effect