Acetaminophen Recruits Spinal p42/p44 MAPKs and GH/IGF-1 Receptors to Produce Analgesia via the Serotonergic System

Bonnefont, Jérôme; Daulhac, Laurence; Etienne, Monique; Chapuy, Eric; Mallet, Christophe; Ouchchane, Lemlih; Deval, Christiane; Courade, Jean-Philippe; Ferrara, Marc; Eschalier, Alain; Clottes, Eric

doi:10.1124/mol.106.025775

Cited by 36 publications

(15 citation statements)

References 46 publications

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“…Serotonin (also known as 5-hydroxytryptamine, 5-HT) exerts effects via several subtypes of its cognate receptor, and its localization in axon termini places these subtypes in prime location for the modulation of pain, transmission and processing (42,43). Previous studies have reported that acetaminophen may exert antinociceptive effect through increasing the levels of serotonin released from serotonergic neurons in the brainstem, known as central mediation (42,43). Furthermore, results have suggested that acetaminophen acts directly on the opioid receptor or cannabinoid (CB) receptor, or indirectly by increasing levels of the endogenous ligands including opioid or anandamide (44,45).…”

Section: Discussionmentioning

confidence: 99%

Enhanced analgesic effects of nefopam in combination with acetaminophen in rodents

Zhuang

et al. 2017

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Abstract. Nefopam, an analgesic drug, effectively elicits antinociception in the majority of noxious and thermal models in rodents. Acetaminophen is among the most commonly used analgesic and antipyretic drugs worldwide, either on prescription or over the counter. The present study aimed to investigate the analgesic activity of nefopam combined with acetaminophen, which was expected to maximize the potency of analgesia and decrease the dose of nefopam required. Three series of experiments, namely acetic acid-induced writhing tests in mice, hot plate tests in mice and tail flick tests in rats, were used to evaluate the analgesic effect. Initially, an optimum proportion of the two drugs, 3.5 mg/kg nefopam (N) + 60 mg/kg acetaminophen (A), was determined by orthogonal array design based on writhing response number. Subsequently, combinations of N and A (1.75 N + 30 A, 3.5 N + 60 A and 7.0 N + 120 A mg/kg) were determined to elicit antinociception in the writhing test (P<0.01 vs. normal saline control) in a dose-dependent manner. In the hot plate test, hot plate latencies up to 60 min after drug treatment were observed. The combination of 7.0 N + 120 A mg/kg exerted a greater cumulative antinociceptive effect throughout the observation period, with an area under the curve value of 1,156.95±199.30 area units (AU), compared with that achieved by 7.0 N mg/kg alone (632.12±62.38 AU). Furthermore, both monotherapy and compound therapy exhibited antinociception dose-dependently in the tail-flick test. However, a combination of 5.0 N + 84 A mg/kg exerted greater analgesic effect compared with 5.0 N mg/kg alone. The data obtained demonstrate that acetaminophen may enhance the antinociceptive activity of nefopam. Thus, coadministration of nefopam with acetaminophen warrants clinical evaluation.

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Section: Discussionmentioning

confidence: 99%

Enhanced analgesic effects of nefopam in combination with acetaminophen in rodents

Zhuang

et al. 2017

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“…The molecular mechanism underlying acetaminophen-induced analgesia via the serotonergic system was recently studied [68]. Acetaminophen modulated the expression of four genes in the lumbar enlargement of the rat spinal cord following the formalin test, but not in naive rats.…”

Section: The Serotonergic System and Its Relation To Non-opioidsmentioning

confidence: 99%

Mechanisms of Non-Opioid Analgesics Beyond Cyclooxygenase Enzyme Inhibition

Hamza¹,

Dionne²

2009

CMP

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Non-opioid analgesics including both selective and non-selective cyclooxygenase (COX) inhibitors and acetaminophen are the most widely used treatments for pain. Inhibition of COX is thought to be largely responsible for both the therapeutic and adverse effects of this class of drugs. Accumulating evidence over the past two decades has demonstrated effects of non-opioids beyond the inhibition of COX and prostaglandin synthesis that might also explain their therapeutic and adverse effects. These include their interaction with endocannabinoids, nitric oxide, monoaminergic, and cholinergic systems. Moreover, the recent development of microarray technology that allows the study of human gene expression suggests multiple pathways that may be related to the analgesic and antiinflammatory effects of non-opioids. The present review will discuss the multiple actions of nonopioids and their interactions with these systems during inflammation and pain, suggesting that COX inhibition is an incomplete explanation for the actions of non-opioids and proposes the involvement of multiple selective targets for their analgesic, as well as, their adverse effects.

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“…After 2 days, the cells were collected and hRFPL1 expression was assessed by semiquantitative end-point PCR as previously described 43 or by real-time PCR as described below.…”

Section: Methodsmentioning

confidence: 99%

Primate-specific RFPL1 gene controls cell-cycle progression through cyclin B1/Cdc2 degradation

et al. 2010

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Ret finger protein-like 1 (RFPL1) is a primate-specific target gene of Pax6, a key transcription factor for pancreas, eye and neocortex development. However, its cellular activity remains elusive. In this article, we report that Pax6-elicited expression of the human (h)RFPL1 gene in HeLa cells can be enhanced by in vivo p53 binding to its promoter and therefore investigated the hypothesis that hRFPL1 regulates cell-cycle progression. Upon expression in these cells, hRFPL1 decreased cell number through a kinase-dependent mechanism as PKC activates and Cdc2 inhibits hRFPL1 activity. hRFPL1 antiproliferative activity led to an increased cell population in G 2 /M phase and specific cyclin B1 and Cdc2 downregulations, which were precluded by a proteasome inhibitor. Specifically, cytoplasm-localized hRFPL1 prevented cyclin B1 and Cdc2 accumulation during interphase. Consequently, cells showed a delayed entry into mitosis and cell-cycle lengthening resulting from a threefold increase in G 2 phase duration. Given previous reports that RFPL1 is expressed during cell differentiation, its impact on cell-cycle lengthening therefore provides novel insights into primate-specific development. The human Ret finger protein-like (hRFPL)1,2,3 genes (OMIM 605968, 605969, 605970) are recently identified targets of Pax6, which is notably a key transcription factor for pancreas, eye and neocortex development. [1][2][3] In this line, high hRFPL1,2,3 expression is found at the onset of neurogenesis in differentiating embryonic stem cells and in the developing neocortex. 4 In addition, the study of RFPL1,2,3 evolutionary history revealed that they are only found in Old World monkeys and great apes and show features believed to be important for human brain evolution. 4 Yet, the cellular activity of RFPL1,2,3 is still unknown. A murine RFPL (mRFPL) protein, encoded by an ancestral gene not belonging to the RFPL1,2,3 gene subfamily, 4 has also been cloned. 5 Previously reported as being expressed only in testis, ovaries and oocytes, 5,6 mRFPL has been shown to interact with the destruction box motif of cyclin B1 -the Cdc2 activating partner for driving germ cells through metaphases I and II 7 -and with proteins of the proteasome, speculating on mRFPL ability to elicit cyclin B1 degradation to control meiosis progression. 6 However, the fact that cyclin B1 and Cdc2 also form a key complex for controlling cell entry into mitosis 8 and our recent observations that the RFPL genes are also expressed in tissues in which cells divide mitotically 4 suggest that the RFPL proteins could regulate other aspects of cell division.We therefore examined RFPL-mediated control of mitotic cell-cycle progression by focusing on hRFPL1. Because no endogenously hRFPL1-expressing cell type suitable for this kind of study has been reported to date, we examined the influence of hRFPL1 gain of function on HeLa cells, a reference cell system for examining cell-cycle regulation. We report that hRFPL1 is an antiproliferative gene that controls G 2 -M phase transition, ...

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Acetaminophen Recruits Spinal p42/p44 MAPKs and GH/IGF-1 Receptors to Produce Analgesia via the Serotonergic System

Cited by 36 publications

References 46 publications

Enhanced analgesic effects of nefopam in combination with acetaminophen in rodents

Enhanced analgesic effects of nefopam in combination with acetaminophen in rodents

Mechanisms of Non-Opioid Analgesics Beyond Cyclooxygenase Enzyme Inhibition

Primate-specific RFPL1 gene controls cell-cycle progression through cyclin B1/Cdc2 degradation

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