Mitogen-Activated Protein Kinase Signaling Mediates Morphine Induced-Delayed Hyperalgesia

Abstract

The use of morphine, the standard opioid drug, is limited by its undesirable effects, such as tolerance, physical dependence, and hyperalgesia (increased pain sensitivity). Clinical and preclinical studies have reported development of hyperalgesia after prolonged opioid administration or after a single dose of intrathecal (i.t.) morphine in uninjured rats. However, whether a single standard systemic morphine dose is sufficient to decrease the nociceptive threshold in rats is unknown. Here, we showed that a single morphine subcutaneous injection induces analgesia followed by a long-lasting delayed hyperalgesia in uninjured and PGE2 sensitized rats. The i.t injection of extracellular signal-regulated kinase (ERK) inhibitor blocked morphine-induced analgesia, without interfering with the morphine-induced hyperalgesia. However, i.t. injection of SB20358, a p38 inhibitor and SP660125, a JNK inhibitor, decreased the morphine-induced hyperalgesia. Consistently with the behavioral data, Western Blot analysis showed that ERK is more phosphorylated 1 h after morphine, i.e., when the analgesia is detected. Moreover, phospho-p38 and phospho-JNK levels are upregulated 96 h after morphine injection, time that coincides with the hyperalgesic effect. Intrathecal (i.t.) oligodeoxynucleotide (ODN) antisense to cAMP-responsive element binding protein (CREB) attenuated morphine-induced hyperalgesia. Real-time polymerase chain reaction (RT-PCR) analysis showed that CREB downstream genes expressions were significantly up-regulated 96 h after morphine injection in spinal cord. Together, our data suggest that central ERK is involved in the analgesic and hyperalgesic effects of morphine while JNK, p38, and CREB are involved in the morphine-induced delayed hyperalgesia.

Morphine Addiction and Oxidative Stress: The Potential Effects of Thioredoxin-1

“…Although mechanisms underlying morphine-mediated processes remain the subject of much debate, morphine stimulation activates G protein-coupled opioid receptors and then induces significant molecular changes inside the cell, such as an inhibition of adenylate cyclase activity, and activation of potassium channels (Qu et al, 2017;Yang et al, 2019). In addition, other signalling pathways, including mitogenactivated kinases (MAPK), b-arrestin, phospholipase C, protein kinase, PI3K, and extracellular signal-regulated kinase (ERK) pathways, are also involved in morphine activity (Bianchi et al, 2010;Zhang and Pan, 2010;Dai et al, 2018;Shen et al, 2018;de Freitas et al, 2019;Dekan et al, 2019;Listos et al, 2019). Recently, the role of oxidative stress in morphine action has been paid more attention.…”

PKCζ-Mitogen-Activated Protein Kinase Signaling Mediates Crotalphine-Induced Antinociception

“…In order to investigate the potential mechanisms involved in the antinociception induced by systemic crotalphine, we sought to determine whether crotalphine interferes with the expression and phosphorylation of ERK, JNK and p38 (Figure 2A). Importantly, since the inhibition of MEK, an up-stream MAPK kinase, blocks PGE 2 induced hyperalgesia, the following experiments were conducted in naïve rats, i.e., without sensitization to focus on the mechanism involved in crotalphine-induced analgesia [7]. Moreover, we selected the 1 µg/kg dose of crotalphine for the next experiments.…”

“…In this regard, peripheral inflammation or nerve injury are followed by spinal activation of ERK1/2, JNK and p38 that seems to increase neuronal excitability and up-regulate transcriptional factors involved in nociception [5]. However, the ERK1/2-signaling activation is essential for morphine and KOR agonists-mediated analgesia in rodents, suggesting that ERK activation may also positively affect the pain outcome [6,7].…”

Acute morphine blocks spinal respiratory motor plasticity via long‐latency mechanisms that require toll‐like receptor 4 signalling

“…Although downstream effectors of TLR4 signalling in the context of opioid use are not fully known, TLR4-mediated p38 mitogen-activated protein kinase (MAPK) activation initiates pro-inflammatory cascades, resulting in aberrant modulation of neural function (Hutchinson et al 2008a(Hutchinson et al , 2011Chen & Sommer, 2009;Winters et al 2017;de Freitas et al 2019;Deng et al 2019). P38 MAPK signalling is often associated with stimuli that are inflammatory or stressful and its activation is an important regulator of neural synaptic plasticity (Thomas & Huganir, 2004;Moult et al 2008;Collingridge et al 2010).…”