Nitric Oxide Synthase Modulates the Antihyperalgesic Effect of the NMDA Receptor Antagonist MK-801 on Carrageenan-Induced Inflammatory Pain in Rats

Abstract

The N-methyl-d-aspartate (NMDA) receptor, an ionotropic glutamate receptor, may play a significant role in the development and maintenance of an inflammatory pain. Activation of NMDA receptors may cause nitric oxide (NO) release through activation of NO synthase (NOS). MK-801, a noncompetitive NMDA receptor antagonist is commonly used as a neuropharmacological tool. The interaction between MK-801 and NOS in the inflammatory pain has not been evaluated before. We investigated whether MK-801 affects inflammatory pain and whether NOS modulates the effect of MK-801. Carrageenan-induced hyperalgesia was evaluated by measuring the withdrawal response to mechanical stimuli, using an electronic version of the von Frey anesthesiometer in Wistar rats. MK-801 given subcutaneously (0.5-20 μg/kg) or intraplantarly (0.1 and 0.15 μg/paw) significantly reduced mechanical hyperalgesia. Intraplantarly given MK-801 exerted a local antihyperalgesic effect, because when applied to the contralateral side it did not reduce mechanical sensitivity in the ipsilateral side. N-nitro-L-arginine methyl ester hydrochloride (5 and 10 mg/kg), a non-selective NOS inhibitor, significantly reduced the effects of MK-801. N-ω -Propyl-L-arginine hydrochloride (0.5-2 mg/kg), a selective inhibitor of neuronal NOS, increased the antihyperalgesic effect of MK-801, whereas S-methylisothiourea (5-15 μg/kg), a selective inhibitor of inducible NOS, lowered the antihyperalgesic effect of MK-801. Importantly, each NOS inhibitor given alone did not affect carrageenaninduced hyperalgesia. In conclusion, MK-801 is effective against inflammatory pain and its antihyperalgesic effect is modulated in a different ways by NOS, being enhanced by a neuronal NOS inhibitor but reduced by an inducible NOS inhibitor.

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

“…did not change the antinociceptive effects of magnesium sulfate and dizocilpine. In our previous study, SMT, an inducible nitric oxide synthase inhibitor, was effective at a later time-point than L-NPA (Srebro et al 2014a(Srebro et al , 2014b. It is possible that the short duration of the observation period is the reason why we obtained different results those reported in our previous study.…”

“…It is known that nitric oxide is involved in somatic and visceral pain modulation, both in the CNS and peripheral nervous systems, in somatic and visceral pain (Bulutcu et al 2002, Freire et al 2009, Srebro et al 2014a, 2014b. Nitric oxide plays both nociceptive and antinociceptive roles.…”

“…Given that the use of these drugs is accompanied by side effects, it is necessary to develop novel analgesics with less side effects. Previous experiments conducted in our laboratory demonstrated the analgesic effect of magnesium sulfate and dizocilpine (MK-801) in different models of nociception, such as the carrageenan-induced somatic (Srebro et al 2014a(Srebro et al , 2014b and acetic acid-induced visceral inflammatory pain models . However, the mechanisms responsible for the effects of magnesium and dizocilpine remain unknown.…”

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

“…The carrageenan-induced pain test assesses the spinal response to pain by measuring the paw withdrawal reflex threshold following exposure to a mechanical stimulus. We conducted the test as previously described in detail ( Srebro et al, 2014a , b ). In brief, the von Frey filament was applied to the plantar surface of the tested paw until the paw withdrawal threshold occurred.…”

Investigation of mucus obtained from different fish species on the acute pain induced with scalpel incision in paw of rats

“…The fish species used in this study included the Oncorhynchus mykiss, Salvelinus fontinalis, Salmo coruhensis, Acipenser gueldenstaedtii, and Acipenser baerii, and the fish were raised at the RTEU Fisheries Research and Practise Center. As is widely know, analgesic activity can be induced in rats using formalin, carrageenan, and other methods [ 9 , 10 , 11 , 12 ]. The postoperative pain model used in this study was created with scalpel incision in the paw of rats [ 13 ].…”