The Regulatory Role of Nitric Oxide in Morphine-Induced Analgesia in the Descending Path of Pain From the Dorsal Hippocampus to the Dorsolateral Periaqueductal Gray Publisher Pubmed



Hashemi M¹ ; Karami M¹ ; Zarrindast M²
Source: European Journal of Pain (United Kingdom) Published:2022

Abstract

Background: Nitric oxide (NO) levels in brain nuclei, such as the hippocampus and brainstem, are involved in morphine analgesia, but the relationship between the dorsal hippocampus (dH) and the dorsolateral periaqueductal gray matter (dlPAG) needs to be clarified, which is our goal. Methods: Wistar rats were simultaneously equipped with a stereotaxic device with unilateral guide cannula at dH and dlPAG. After recovery, they were divided into control and experimental groups. Formalin (50 μl of 2.5%) was inoculated into the left hind paw of the rat. Morphine (6 mg/kg) was administered intraperitoneally (i.p.) 10 min before formalin injection. L-Arginine (0.25, 0.5, 1 and 2 μg/rat), and L-NAME (0.25, 0.5, 1 and 2 μg/rat), unrelatedly or with respect in the order of injection were used in the nuclei before morphine injection (i.p.). Activation of the neuronal NO synthase (nNOS) in the brains of all animals was measured using NADPH-diaphorase, a selective biochemical marker of nNOS. Results: Morphine reduced inflammatory pain in the early and late stages of the rat formalin test. The morphine response was attenuated before injection of single L-arginine but not L-NAME in the two target areas. However, the acute phase result was stopped due to L-NAME pretreatment. When L-NAME was injected into dlPAG before injecting L-arginine at dH, the morphine response did not decrease at all, indicating a modulatory role of NO in dlPAG, which was confirmed by NADPH-d staining. Conclusions: High levels of NO in dlPAG may regulate the pain process in downward synaptic interactions. Significance: Nitric oxide is involved in the dH and dlPAG in morphine-induced analgesia in the rat formalin test. Morphine has analgesic effects in both phases of the rat formalin test. The morphine response is reduced in two stages by injection of the NO precursor L-arginine but not the nNOS inhibitor L-NAME in the dH and dlPAG. By injecting L-NAME before L-arginine in both nuclei, the morphine-induced response returns in the early stages. Due to the initial injection of L-NAME into dlPAG and the subsequent injection of L-arginine at dH, morphine analgesia is not reduced at all, indicating NO modulation in the pain pathway from dH to dlPAG. © 2022 European Pain Federation - EFIC®.