Inhibition of neuronal and inducible nitric oxide synthase does not affect the analgesic effects of NMDA antagonists in visceral inflammatory pain

Abstract

Previously we described the antinociceptive effect of magnesium sulfate and dizocilpine in the visceral and somatic rat models of pain. In the somatic model of pain, we established the influence of selective inhibitors of neuronal and inducible nitric oxide synthase on the antihyperalgesic effects of magnesium sulfate and dizocilpine. Therefore, the objective of the present study was to determine in the rat model of visceral pain whether same mechanisms are involved in the antinociceptive action of magnesium sulfate and dizocilpine.Analgesic activity was assessed using the acetic acid-induced writhing test in rats. Subcutaneous injection of either magnesium sulfate (15 mg/kg) or dizocilpine (0.01 mg/kg) decreased the number of writhes by about 60 and 70%, respectively. The role of nitric oxide on the effects of magnesium sulfate and dizocilpine was evaluated using selective inhibitor of neuronal [N-ω-Propyl-L-arginine hydrochloride (L-NPA)] and inducible [S-methylisothiourea (SMT)] nitric oxide synthase, which per se did not affect the number of writhes. We observed that the antinociceptive effect of magnesium sulfate or dizocilpine did not change in the presence of L-NPA (2 and 10 mg/kg, i.p.) and SMT (0.015 and 10 mg/kg, i.p.). We conclude that, nitric oxide produced by neuronal and inducible nitric oxide synthase does not modulate the effects of magnesium sulfate and dizocilpine in the visceral inflammatory model of pain in the rat.

Pellucidin A promotes antinociceptive activity by peripheral mechanisms inhibiting COX-2 and NOS: In vivo and in silico study

“…LaBuda et al [32] showed that iNOS is involved in the acetic acid test in mice since the systemic administration of an iNOS inhibitor reduced the number of writhings. However, in a rat model, iNOS and nNOS inhibition does not seem to affect the number of writhings [33]. Nevertheless, in our mice and in silico model, we showed that Pellucidin A has the potential to act through interaction with NOS, indicating that iNOS plays a potential role in Pellucidin A antinociception function.…”

The Interactions of Magnesium Sulfate and Cromoglycate in a Rat Model of Orofacial Pain; The Role of Magnesium on Mast Cell Degranulation in Neuroinflammation

“…It is possible that the effect of magnesium dominates. Magnesium at low doses does not reduce “pure” nociceptive pain, and at the same time, activates TRP channels, vanilloid (TRPV1 and TRPV4), and ankyrine (TRPA1) types and releases glutamate and nitric oxide at the periphery [ 30 , 41 ]. All these mechanisms are responsible for the occurrence of “pure” nociceptive pain [ 42 , 43 , 44 ], and magnesium probably, in this way, enhances the pain in the early phase of the formalin test.…”

“…In combination with opioids or N-methyl-D-aspartate (NMDA) antagonists, magnesium increases their analgesic effect in inflammatory and neuropathic pain [ 26 , 27 , 28 ]. The mechanisms of the analgesic effect of magnesium include the blockade of NMDA receptors, modulation of the production of nitric oxide, and activation of transient receptor potential (TRP) channels vanilloid type 1 and 4 and ankyrin type 1 [ 24 , 25 , 26 , 29 , 30 ]. Recent data show that peripheral NMDA receptors located on peripheral sensory trigeminal ganglion neurons have magnesium-dependent mechanisms of action, contributing to the pathophysiology of migraines [ 31 ].…”

Evaluation of Prophylactic and Therapeutic Effects of Tramadol and Tramadol Plus Magnesium Sulfate in an Acute Inflammatory Model of Pain and Edema in Rats

“…There are many possible mechanisms for the analgesic effect of magnesium, such as: (1) Ca ++ channel blocking, (2) decreasing the effects of acetylcholine on muscle receptors and increasing the threshold of axonal excitation (Dubé and Granry, 2003), (3) antagonism of NMDA receptors, (4) activation of transient receptor potential cation channel vanilloid type 1 (TRPV1), vanilloid type 4 (TRPV4), ancyrin type 1 (TRPA1) proteins ( Srebro et al, 2016b ), (5) NMDA-independent nitric oxide modulation of the antihyperalgesic effects of magnesium sulfate in inflammatory pain ( Vuckovic et al, 2015 ; Srebro et al, 2014a , b , 2016a ), (6) reducing inflammatory edema, and (7) an additional antiinflammatory mechanism ( Aryana et al, 2014 ). A meta-analysis of randomized, controlled trials that included over 1,000 patients revealed that perioperative magnesium administration reduced both pain and opioid consumption ( De Oliveira et al, 2013 ).…”

“…Magnesium reduces inflammatory pain as both a prophylactic and therapeutic drug ( Srebro et al, 2014a ). The analgesic effect of magnesium in inflammatory pain is achieved by modulating nitric oxide synthesis ( Srebro et al, 2014a , Vuckovic et al, 2015 ; Srebro et al, 2016a ). In the general population, magnesium is a widely used dietary supplement, and it could potentially interact with other drugs, such as antibiotics ( Adepoju-Bello et al, 2008 ).…”