The analgesic effect of N-arachidonoyl-serotonin, a FAAH inhibitor and TRPV1 receptor antagonist, associated with changes in rostral ventromedial medulla and locus coeruleus cell activity in rats

Novellis, Vito de; Palazzo, Enza; Rossi, Francesca; Petrocellis, Luciano De; Petrosino, Stefania; Guida, Francesca; Luongo, Livio; Migliozzi, Annalucia; Cristino, Luigia; Marabese, Ida; Starowicz, Katarzyna; Marzo, Vincenzo Di; Maione, Sabatino

doi:10.1016/j.neuropharm.2008.06.023

Cited by 45 publications

(31 citation statements)

References 46 publications

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Section: Discussionmentioning

confidence: 91%

“…In WKY rats, intra-VLPAG 5'-IRTX Thus the authors propose that a PAG -LC -spinal cord pathway may be implicated in the effects of intra-VLPAG AA-5HT (de Novellis et al, 2008). Moreover, intra-VLPAG AA-5-HT prevented the changes in ON and OFF cell firing activity induced by intra-plantar formalin injection, and it prevented the formalin-induced increase in LC noradrenergic cell activity (de Novellis et al, 2008). In a more recent study, Liao et al reported that capsaicin, when injected into the VLPAG, increased paw withdrawal latency in the hot plate test in Wistar rats (Liao et al, 2011), similar to the capsaicininduced reduction in formalin-evoked nociceptive behaviour in SD rats observed in the present study.…”

Section: Discussionmentioning

confidence: 99%

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Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey

Madasu

Okine

Olango

et al. 2016

Pharmacological Research

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey

Madasu

Okine

Olango

et al. 2016

Pharmacological Research

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“…ON cell facilitation may be sufficiently effective that a reduction in ON cell activity alone is antinociceptive. Indeed, supraspinal administration of several nonopioid compounds suppresses evoked ON cell bursts (while depressing the spontaneous discharge of ON and OFF cells) and increases tail flick latency in anesthetized rats (de Novellis et al, 2008(de Novellis et al, , 2012Maione et al, 2011). As withdrawal magnitudes were not measured in these studies, it is unclear whether magnitudes were decreased.…”

Section: The On Cell Burst Shapes Motor Withdrawalsmentioning

confidence: 94%

Opioids Disrupt Pro-Nociceptive Modulation Mediated by Raphe Magnus

Hellman

Mason

2012

J. Neurosci.

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In anesthetized rats, opioid analgesia is accompanied by a specific pattern of tonic activity in two neuronal populations within the medullary raphe magnus (RM): opioids silence pain-facilitatory ON cells and produce sustained discharge in pain-inhibitory OFF cells. These tonic activity patterns, hypothesized to generate a tonic analgesic state, have not been observed in recordings made without anesthesia. Therefore, we recorded ON and OFF cell activity before and after an analgesic dose of morphine in unanesthetized mice. The tonic activity of ON and OFF cells was unchanged by morphine. Rather, morphine suppressed the phasic ON cell excitation and OFF cell inhibition evoked by noxious stimulation. Before morphine, the magnitude of the noxious stimulus-evoked burst in ON cells correlated with motor withdrawal magnitude, suggesting that ON cells facilitate nocifensive motor reactions. Contrary to model prediction, OFF cell activity was greater before stimulus trials that evoked withdrawals than those without withdrawals. Since withdrawals only occurred when OFF cell activity was suppressed, a decrease in OFF cell activity appears to serve as a pro-nociceptive signal that synchronizes and therefore strengthens the ensuing motor reaction. We further propose that morphine acts in RM to suppress ON and OFF cell phasic responses and thereby disable RM's pro-nociceptive output. Thus, RM cells produce antinociception by failing to exert the pronociceptive effects normally engaged by noxious stimulation. These findings revise the conventional understanding of supraspinal opioid analgesia and demonstrate that RM produces on demand rather than state modulation, allowing RM cells to serve other functions during pain-free periods.

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“…Although these compounds have poor drug-like properties, there have also been a number of in vivo studies with these compounds demonstrating analgesia and other cannabinoid-like effects. AA-5-HT was effective in the formalin test and in the CCI model of neuropathic pain when administered intraperitoneally [132], and also in the formalin test when administered directly into the PAG [133]. A very recent study has also described the anti-inflammatory and antihyperalgesic actions of AA-5-HT in the mouse CFA model of inflammatory pain [134].…”

Section: Substrate-mimetic Faah Inhibitorsmentioning

confidence: 99%

The Role of Endocannabinoids in Pain Modulation and the Therapeutic Potential of Inhibiting their Enzymatic Degradation

Alvarez-Jaimes¹,

Palmer²

2011

CPB

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The need for new pain therapies that provide greater relief without unwanted side-effects drives the search for new drug targets. The identification of endogenous lipid ligands for the two known cannabinoid receptors (CB(1) and CB(2)) has led to numerous studies investigating the role of these endocannabinoids in pain processes. The two most widely studied endocannabinoids are anandamide (AEA; arachidonoyl ethanolamide) and 2-arachidonoylglycerol (2-AG), but there are also a number of structurally related endogenous lipid signaling molecules that are agonists at cannabinoid and noncannabinoid receptors. These lipid signaling molecules are not stored in synaptic vesicles, but are synthesized and released on-demand and act locally, as they are rapidly inactivated. This suggests that there may be therapeutic potential in modulating levels of these ligands to only have effects in active neural pathways, thereby reducing the potential for side-effects that result from widespread systemic cannabinoid receptor activation. One approach to modulate the levels and duration of action of these lipid signaling molecules is to target the enzymes responsible for their hydrolysis. The two main enzymes responsible for hydrolysis of these lipid signaling molecules are fatty acid amide hydrolase (FAAH) and monoacylglyceride lipase (MGL). This article will discuss the role of the endocannabinoid system in the modulation of pain and will review the current understanding of the properties of the hydrolytic enzymes and the recent advances in developing inhibitors for these targets, with particular relevance to the treatment of pain.

show abstract

The analgesic effect of N-arachidonoyl-serotonin, a FAAH inhibitor and TRPV1 receptor antagonist, associated with changes in rostral ventromedial medulla and locus coeruleus cell activity in rats

Cited by 45 publications

References 46 publications

Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey

Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey

Opioids Disrupt Pro-Nociceptive Modulation Mediated by Raphe Magnus

The Role of Endocannabinoids in Pain Modulation and the Therapeutic Potential of Inhibiting their Enzymatic Degradation

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