cyclic-gmp and Nociceptive-Pain

The leukotrienes are inflammatory mediators. In the present study, the analgesic role of local montelukast, a cysteinyl leukotriene receptor antagonist, and the possible involvement of L-arginine/NO/cGMP/K. The local administration of montelukast into the hind paw produced dose-related analgesia during both phases of the formalin test. Furthermore, pre-treatment with L-NAME, methylene blue, and glibenclamide prevented montelukast (10 μg/paw)-induced antinociception in both early and late phases of the test. Moreover, the local L-arginine and diazoxide before the sub-effective dose of montelukast (3 μg/paw) produced an analgesic effect. Also, local GW-9662 blocked antinociception induced by montelukast plus pioglitazone (10 μg/paw).. In conclusion, montelukast produced peripheral analgesia through PPARγ receptors and activation of the L-arginine/NO/cGMP/K

Topics: Acetates; Analgesia; Analgesics; Animals; Arginine; Behavior, Animal; Cyclic GMP; Cyclopropanes; Disease Models, Animal; KATP Channels; Leukotriene Antagonists; Male; Nitric Oxide; Nociceptive Pain; PPAR gamma; Quinolines; Rats, Wistar; Signal Transduction; Sulfides

Severe pain reduces quality of life of patients with various diseases, often because chronic morphine therapy results in reduced analgesic effectiveness, or tolerance, leading to escalating doses and distressing adverse effects. Nitric oxide (NO) plays a role in morphine tolerance and dependence.. Venlafaxine, an antidepressant, is known to modulate nitric oxide (NO) pathway in nervous tissues. In the present study, the effect of systemic venlafaxine (VLF) on the development of morphine tolerance and dependence, acute morphine-induced antinociception, and the probable involvement of the L-arginine/NO/cGMP pathway in these effects were investigated in mice.. Animals developed tolerance to the antinociceptive effect of morphine (50 mg/kg, s.c. daily) for 3 consecutive days. NO modulators like L-NAME (NO synthase inhibitor) and L-Arginine (L-Arg, substrate for NO synthase), sildenafil (cGMP-PDE inhibitor) alone or in combination with venlafaxine were used.. The results showed that i.p. administration of VLF (5-40 mg/kg) produced antinociceptive effect in a dose-dependent way. Pretreatment with L-Arg (200 mg/kg, i.p.) reversed the antinociception and L-NAME (30 mg/kg, i.p.) and sildenafil (10 mg/kg, i.p.) potentiated the antinociceptive effect. Moreover, co-administration of VLF in non-effective dose (5 mg/kg) with morphine, potentiated acute morphine-induced analgesia (5 mg/kg, s.c.). This effect was antagonized by L-arginine (200 mg/kg, i.p.) and potentiated by L-NAME (30 mg/kg, i.p.) and sildenafil (10 mg/kg, i.p.). On the other hand, VLF was prevented the development of morphine antinociceptive tolerance and dependence. These effects were antagonized by L-arginine (200 mg/kg, i.p.) and potentiated by L-NAME (30 mg/kg, i.p.) and sildenafil (10 mg/kg, i.p.).. Our data suggest that the combination of VLF with morphine may be a relevant therapeutic implication to manage pain even when tolerance to morphine exists. Moreover, our data demonstrates the involvement of L-Arg/NO/cGMP pathway in the prevention of morphine tolerance and dependence by venlafaxine.

Topics: Analgesics, Opioid; Animals; Arginine; Behavior, Animal; Brain; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Male; Mice; Morphine; Morphine Dependence; Nitric Oxide; Nociceptive Pain; Signal Transduction; Time Factors; Venlafaxine Hydrochloride

Nitric oxide has been proven to play an important role in nociception, accordingly, its promoters, phosphodiesterase inhibitors have been investigated as pain response modulators. Aiming to evaluate the central antinociceptive effect of tadalafil, a phosphodiesterase 5 inhibitor, and to determine its EC50, tail flick and hot plate tests were employed. On the other hand, tadalafil antinociceptive peripheral effect was assessed through acetic acid-induced writhing model. Formalin test was used to appraise both non-inflammatory and inflammatory pain responses. In order to elaborate the involvement of opioid receptors and nitric oxide/cyclic guanosine monophosphate/potassium-ATP pathway in tadalafil-induced analgesia, mice were pretreated with naloxone, l-nitro-arginine-methyl-ester (l-NAME), methylene blue, and glibenclamide. The results illustrated that tadalafil had a significant antinociceptive effect in the tail flick, hot plate, acetic acid-induced writhing and formalin tests indicating the involvement of peripheral and central analgesic mechanisms. Moreover, tadalafil mechanism of action involved several receptors and mediators, specifically NO/cGMP pathway and opioid receptors. In the formalin test, naloxone significantly blocked the effect of tadalafil in the first phase and partially in the second phase which is an inflammatory pain-dependent aspect. l-NAME, methylene blue and glibenclamide partially blocked the effect of tadalafil in the first phase and enhanced its effect in the second phase which is related to nitric oxide role in the inflammatory process. As a conclusion, tadalafil possesses a potential analgesic effect via the involvement of opioid and nitric oxide pathways.

Topics: Analgesics; Animals; Behavior, Animal; Cyclic GMP; Disease Models, Animal; Male; Mice, Inbred BALB C; Nitric Oxide; Nociceptive Pain; Pain Threshold; Receptors, Opioid; Second Messenger Systems; Tadalafil

Endogenous carbon monoxide (CO), which is produced by the enzyme heme oxygenase (HO), participates as a neuromodulator in physiological processes such as thermoregulation and nociception by stimulating the formation of 3',5'-cyclic guanosine monophosphate (cGMP). In particular, the acute physical restraint-induced fever of rats can be blocked by inhibiting the enzyme HO. A previous study reported that the HO-CO-cGMP pathway plays a key phasic antinociceptive role in modulating noninflammatory acute pain. Thus, this study evaluated the involvement of the HO-CO-cGMP pathway in antinociception induced by acute stress in male Wistar rats (250-300 g; n=8/group) using the analgesia index (AI) in the tail flick test. The results showed that antinociception induced by acute stress was not dependent on the HO-CO-cGMP pathway, as neither treatment with the HO inhibitor ZnDBPG nor heme-lysinate altered the AI. However, antinociception was dependent on cGMP activity because pretreatment with the guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxaline-1-one (ODQ) blocked the increase in the AI induced by acute stress.

Topics: Acute Pain; Animals; Carbon Monoxide; Cyclic GMP; Deuteroporphyrins; Heme; Heme Oxygenase (Decyclizing); Lysine; Male; Nociceptive Pain; Oxadiazoles; Pain Measurement; Rats, Wistar; Signal Transduction; Stress Disorders, Traumatic, Acute

Citronellal is a monoterpene present in the oil of many species, including Cymbopogon winterianus Jowitt (Poaceae).. The present study investigated the effect of citronellal on inflammatory nociception induced by different stimuli and examined the involvement of the NO-cGMP-ATP-sensitive K⁺ channel pathway.. We used male Swiss mice (n = 6 per group) that were treated intraperitoneally with citronellal (25, 50 or 100 mg/kg) 0.5 h after the subplantar injection of 20 μl of carrageenan (CG; 300 µg/paw), tumor necrosis factor-α (TNF-α; 100 pg/paw), prostaglandin E₂ (PGE₂; 100 ng/paw) or dopamine (DA; 30 μg/paw). The mechanical nociception was evaluated at 0.5, 1, 2 and 3 h after the injection of the agents, using a digital analgesimeter (von Frey). The effects of citronellal were also evaluated in the presence of L-NAME (30 mg/kg) or glibenclamide (5 mg/kg).. At all times, citronellal in all doses inhibited the development of mechanical nociception induced by CG (p < 0.001 and p < 0.01) and TNF-α (p < 0.001, p < 0.01, and p < 0.05). The citronellal was able to increase the pain threshold in the DA test (p < 0.001, p < 0.01, and p < 0.05) and in the PGE₂ test at all times (p < 0.001 and p < 0.05). L-NAME and glibenclamide reversed the antinociceptive effects of the citronellal at higher doses in the PGE₂ test.. These data suggest that citronellal attenuated mechanical nociception, mediated in part by the NO-cGMP-ATP-sensitive K⁺ channel pathway.

Topics: Acyclic Monoterpenes; Aldehydes; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclic GMP; Cymbopogon; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glyburide; Indonesia; KATP Channels; Male; Mice; Monoterpenes; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nociceptive Pain; Oils, Volatile; Pain Threshold; Plant Oils; Potassium Channel Blockers; Signal Transduction