Role of TRPV1 channels of the dorsal periaqueductal gray in the modulation of nociception and open elevated plus maze-induced antinociception in mice

Mascarenhas, Diego Cardozo; Gomes, Keila Rejane Oliveira; Nunes-de-Souza, Ricardo Luiz

doi:10.1016/j.bbr.2015.07.023

Cited by 7 publications

(15 citation statements)

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“…42 Furthermore, activation of TRPV1 within the dorsolateral and ventrolateral PAG reduces thermal hyperalgesia. 31,48–50 Given that the analgesic effects of centrally administered FABP inhibitor were mediated by TRPV1, we examined whether FABP5 and TRPV1 co-localize within the PAG. Indeed, we observed robust expression of FABP5 in the PAG, which co-localized with TRPV1 (Figure 8(a) and (b)).…”

Section: Resultsmentioning

confidence: 99%

Fatty-acid-binding protein inhibition produces analgesic effects through peripheral and central mechanisms

et al. 2017

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BackgroundFatty-acid-binding proteins (FABPs) are intracellular carriers for endocannabinoids, N-acylethanolamines, and related lipids. Previous work indicates that systemically administered FABP5 inhibitors produce analgesia in models of inflammatory pain. It is currently not known whether FABP inhibitors exert their effects through peripheral or central mechanisms. Here, we examined FABP5 distribution in dorsal root ganglia and spinal cord and examined the analgesic effects of peripherally and centrally administered FABP5 inhibitors.ResultsImmunofluorescence revealed robust expression of FABP5 in lumbar dorsal root ganglia. FABP5 was distributed in peptidergic calcitonin gene-related peptide-expressing dorsal root ganglia and non-peptidergic isolectin B4-expressing dorsal root ganglia. In addition, the majority of dorsal root ganglia expressing FABP5 also expressed transient receptor potential vanilloid 1 (TRPV1) and peripherin, a marker of nociceptive fibers. Intraplantar administration of FABP5 inhibitors reduced thermal and mechanical hyperalgesia in the complete Freund’s adjuvant model of chronic inflammatory pain. In contrast to its robust expression in dorsal root ganglia, FABP5 was sparsely distributed in the lumbar spinal cord and intrathecal administration of FABP inhibitor did not confer analgesic effects. Administration of FABP inhibitor via the intracerebroventricular (i.c.v.) route reduced thermal hyperalgesia. Antagonists of peroxisome proliferator-activated receptor alpha blocked the analgesic effects of peripherally and i.c.v. administered FABP inhibitor while antagonism of cannabinoid receptor 1 blocked the effects of peripheral FABP inhibition and a TRPV1 antagonist blocked the effects of i.c.v. administered inhibitor. Although FABP5 and TRPV1 were co-expressed in the periaqueductal gray region of the brain, which is known to modulate pain, knockdown of FABP5 in the periaqueductal gray using adeno-associated viruses and pharmacological FABP5 inhibition did not produce analgesic effects.ConclusionsThis study demonstrates that FABP5 is highly expressed in nociceptive dorsal root ganglia neurons and FABP inhibitors exert peripheral and supraspinal analgesic effects. This indicates that peripherally restricted FABP inhibitors may serve as a new class of analgesic and anti-inflammatory agents.

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Section: Resultsmentioning

confidence: 99%

Fatty-acid-binding protein inhibition produces analgesic effects through peripheral and central mechanisms

et al. 2017

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“…Capsaicin, AEA, Tocrisolve TM , 6-IODO, and WIN were purchased from Tocris Cookson, Ballwin, MO, United States and AM251 from Sigma–Aldrich. The doses were based in pilot and previous studies (Maione et al, 2006; Moreira et al, 2007; Mascarenhas et al, 2013, 2015; Batista et al, 2015). The mass weight of each drug necessary for samples of 25 μL in the doses described were as follow: 50 nmol AEA = 2.12 mg; 10 nmol capsaicin = 3.75 mg; 50 nmol WIN = 3.25 mg; 10 nmol AM251 = 6.94 mg; and 3 nmol 6-IODO = 1.57 mg. Evidently, all drugs had to be diluted from this first solution to reach the proper doses.…”

Section: Methodsmentioning

confidence: 99%

“…In this context, several neurotransmitters have been implicated mediating nociception, for instance, opioids (Yaksh and Noueihed, 1985; Jensen and Yaksh, 1989; Cornelio and Nunes-de-Souza, 2009; Morgan et al, 2014), glutamate (Yaksh and Noueihed, 1985; Palazzo et al, 2013; Wilson-Poe et al, 2013), serotonin (Eschalier et al, 1989; Baptista-de-Souza et al, 2014; de Freitas et al, 2014), and endocannabinoids (Meng et al, 1998; Suplita et al, 2005; Olango et al, 2012). More recently, vanilloid compounds, which are known to activate the Transient Receptor Potential Vanilloid – type 1 (TRPV1) channels, emerged as an important neurotransmission system modulating nociception (e.g., McGaraughty et al, 2003; Starowicz et al, 2007; Mascarenhas et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

“…Besides their role in pain modulation on peripheral nervous system (Gewehr et al, 2011), TRPV1 are also found in brainstem areas including the periaqueductal gray matter (PAG) (Cristino et al, 2006). This midbrain structure is highly involved in the modulation of defensive reactions such as fear/anxiety states as well as nociception (e.g., Starowicz et al, 2007; Lisboa and Guimaraes, 2012; Mascarenhas et al, 2013, 2015). …”

Section: Introductionmentioning

confidence: 99%

“…Therefore, CB1-mediated nociception is under a complex modulation and paradoxical effects have been reported (Meng et al, 1998; Meng and Johansen, 2004; Maione et al, 2006). In addition, TRPV1 stimulation causes glutamate release within the RVM which in turn activates the descending inhibitory system, leading to antinociception (Palazzo et al, 2002; Starowicz et al, 2007; Mascarenhas et al, 2015). However, contrasting effects, i.e., hypernociception, have also been reported following TRPV1 stimulation, an action attributed to the capacity of TRPV1 desensitization (McGaraughty et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Blockade of Cannabinoid CB1 Receptors in the Dorsal Periaqueductal Gray Unmasks the Antinociceptive Effect of Local Injections of Anandamide in Mice

et al. 2017

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Divergent results in pain management account for the growing number of studies aiming at elucidating the pharmacology of the endocannabinoid/endovanilloid anandamide (AEA) within several pain-related brain structures. For instance, the stimulation of both Transient Receptor Potential Vanilloid type 1 (TRPV1) and Cannabinoid type 1 (CB1) receptors led to paradoxical effects on nociception. Here, we attempted to propose a clear and reproducible methodology to achieve the antinociceptive effect of exogenous AEA within the dorsal periaqueductal gray (dPAG) of mice exposed to the tail-flick test. Accordingly, male Swiss mice received intra-dPAG injection of AEA (CB1/TRPV1 agonist), capsaicin (TRPV1 agonist), WIN (CB1 agonist), AM251 (CB1 antagonist), and 6-iodonordihydrocapsaicin (6-IODO) (TRPV1 selective antagonist) and their nociceptive response was assessed with the tail-flick test. In order to assess AEA effects on nociception specifically at vanilloid or cannabinoid (CB) substrates into the dPAG, mice underwent an intrinsically inactive dose of AM251 or 6-IODO followed by local AEA injections and were subjected to the same test. While intra-dPAG AEA did not change acute pain, local injections of capsaicin or WIN induced a marked TRPV1- and CB1-dependent antinociceptive effect, respectively. Regarding the role of AEA specifically at CB/vanilloid substrates, while the blockade of TRPV1 did not change the lack of effects of intra-dPAG AEA on nociception, local pre-treatment of AM251, a CB1 antagonist, led to a clear AEA-induced antinociception. It seems that the exogenous AEA-induced antinociception is unmasked when it selectively binds to vanilloid substrates, which might be useful to address acute pain in basic and perhaps clinical trials.

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The mechanisms of protease-activated receptor 2 in mediating pain behaviors through nonselective cation channel signaling

Yue

Wang

Lau

et al. 2020

Preprint

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Background: Activation of purinergic receptor P2X ligand-gated ion channel 3 (P2X3), transient receptor potential vanilloid type 1 (TRPV1), and transient receptor potential ankyrin 1 (TRPA1) by their specific ligands is a major mechanism contributing to magnified pain responses. The relationship between these nonselective cation channels and proteinase-activated receptor 2 (PAR2) activation mediated pain is still to be clarified.Methods: In this study, both in vitro model of dorsal root ganglion (DRG) neurons with PAR2 agonist SL-NH2 challenge and SL-NH2-induced pain rat model were used to approach these questions. The expression of P2X3, TRPV1, and TRPA1 in DRG neurons was investigated by quantitative real-time RT-PCR, Western blot, and immunofluorescence. The involvement of the PLCβ3/PKCε signaling pathway was also determined. The behavior test for mechanical allodynia and thermal hyperalgesia was performed. Results: SL-NH2 induced upregulation of P2X3, TRPV1, and TRPA1 through phosphorylation of phospholipase Cβ3 (PLCβ3) and protein kinase Cε (PKCε) signaling pathway in DRG neurons in vitro and in vivo. SL-NH2 also elevated the proportion of P2X3-, TRPV1-, and TRPA1-expressing neurons. The upregulation of P2X3, TRPV1, and TRPA1 and phosphorylation of PLCβ3 and PKCε in DRG neurons was paralleled with mechanical allodynia and thermal hyperalgesia behaviors in rats. Conclusions: The data of the present study imply that SL-NH2 as a noxious stimulus activates PAR2 which induces TRPV1, TRPA1, and P2X3 upregulation through PLCβ3/PKCε signaling pathway, thereby decreasing activation thresholds and increasing excitability, resulting in sustained nociceptive activity in DRG neurons, and then causing mechanical allodynia and thermal hyperalgesia behaviors. These data expanded our knowledge about PAR2-mediated pain sensitivity and its relationship with TRPV1, TRPA1, and P2X3 and provided new opportunities on management of pain behaviors.

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Role of TRPV1 channels of the dorsal periaqueductal gray in the modulation of nociception and open elevated plus maze-induced antinociception in mice

Cited by 7 publications

References 55 publications

Fatty-acid-binding protein inhibition produces analgesic effects through peripheral and central mechanisms

Fatty-acid-binding protein inhibition produces analgesic effects through peripheral and central mechanisms

Blockade of Cannabinoid CB1 Receptors in the Dorsal Periaqueductal Gray Unmasks the Antinociceptive Effect of Local Injections of Anandamide in Mice

The mechanisms of protease-activated receptor 2 in mediating pain behaviors through nonselective cation channel signaling

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