Plasma Membrane Mechanisms in a Preclinical Rat Model of Chronic Pain

Ferrari, Luiz F.; Levine, Jon D.

doi:10.1016/j.jpain.2014.10.007

Cited by 29 publications

(40 citation statements)

References 36 publications

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“…Mechanical nociceptive threshold was quantified using an Ugo Basile Analgesymeter ® (Randall-Selitto paw-withdrawal test; Stoelting, Chicago, IL), which applies a linearly increasing mechanical force to the dorsum of the rat’s hind paw, as described previously (Taiwo et al, 1989, Taiwo and Levine, 1989, Ferrari and Levine, 2015). Nociceptive threshold was defined as the force in grams at which the animal withdrew its paw; baseline threshold was defined as the mean of 3 readings taken just before a test agent was injected.…”

Section: Methodsmentioning

confidence: 99%

Marked sexual dimorphism in 5-HT 1 receptors mediating pronociceptive effects of sumatriptan

et al. 2017

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Amongst the side effects of triptans, a substantial percentage of patients experience injection site pain and tenderness, the underlying mechanism of which is unknown. We found the dose range from 10 fg – 1000 ng (intradermal) sumatriptan induced a complex dose-dependent mechanical hyperalgesia in the male rat, with distinct peaks, at 1 pg and 10 ng, with no hyperalgesia at 1 ng. In female rats, there was 1 broad peak. The highest dose (1000 ng) did not produce hyperalgesia in either sex. We evaluated the receptors mediating sumatriptan hyperalgesia (1 pg, 1 and 10 ng). In male rats, while the injection of an antagonist for the serotonin (5-hydroxytryptamine, 5-HT) receptor subtype 1B (5-HT1B), but not 5-HT1D, markedly inhibited sumatriptan (1 pg hyperalgesia, at 10 ng a 5-HT1D receptor antagonist completely eliminated hyperalgesia. In contrast, in female rats, the 5-HT1D, but not 5-HT1B, receptor antagonist completely blocked sumatriptan (1 pg and 10 ng) hyperalgesia. Both 5-HT1B and 5-HT1D receptor antagonists attenuated hyperalgesia (1 ng) in females. Sumatriptan (1 ng)-induced hyperalgesia in female rats is G-protein-coupled estrogen receptor 30 dependent. While selective 5-HT1B, but not 5-HT1D, receptor agonists produces a robust hyperalgesia, when co-injected the hyperalgesia induced by 5-HT1B receptor agonist was attenuated. The mechanical hyperalgesia induced by sumatriptan (1 pg and 10 ng) is dependent on the Gi-protein α subunit and protein kinase A (PKA). Understanding the mechanisms responsible for the complex dose dependence for triptan hyperalgesia may provide useful information for the design of anti-migraine drugs with improved therapeutic profiles.

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Section: Methodsmentioning

confidence: 99%

Marked sexual dimorphism in 5-HT 1 receptors mediating pronociceptive effects of sumatriptan

et al. 2017

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“…Mechanical nociceptive threshold was quantified using an Ugo Basile Analgesymeter ® (Randall-Selitto paw-withdrawal test; Stoelting, Chicago, IL), which applies a linearly increasing mechanical force to the dorsum of the rat's hind paw, as previously described [26; 61; 62]. The nociceptive threshold was defined as the force in grams at which the animal withdrew its paw; baseline paw-pressure nociceptive mechanical threshold was defined as the mean of the 3 readings taken just before a test agent was injected.…”

Section: Methodsmentioning

confidence: 99%

Adenosine-A1 receptor agonist induced hyperalgesic priming type II

Araldi

Ferrari

Levine

2016

Pain

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We have recently shown that repeated exposure of the peripheral terminal of the primary afferent nociceptor to the mu-opioid receptor (MOR) agonist DAMGO ([D-Ala2, N-Me-Phe4, Gly5-ol]-Enkephalin acetate salt) induces a model of the transition to chronic pain that we have termed Type II hyperalgesic priming. Similar to Type I hyperalgesic priming, there is a markedly prolonged response to subsequent administration of proalgesic cytokines, prototypically prostaglandin E2 (PGE2). However, Type II hyperalgesic priming differs from Type I in being rapidly induced, protein kinase A (PKA), rather than PKCε dependent, not reversed by a protein translation inhibitor, occurring in female as well as in male rats, and isolectin B4-negative neuron dependent. We report that as with the repeated injection of a MOR agonist, the repeated administration of an agonist at the A1-adenosine receptor, also a Gi-protein coupled receptor, N6-Cyclopentyladenosine (CPA), also produces priming similar to DAMGO-induced Type II hyperalgesic priming. In this study we demonstrate that priming induced by repeated exposure to this A1-adenosine receptor agonist shares the same mechanisms as MOR-agonist induced priming. However, the prolongation of PGE2 hyperalgesia induced by repeated administration of CPA depends on G-protein αi subunit activation, differently from DAMGO-induced Type II priming, in which it depends on the β/γ subunit. These data implicate a novel form of Gi-protein signaling pathway in the Type II hyperalgesic priming induced by repeated administration of an agonist at A1-adenosine receptor to the peripheral terminal of the nociceptor.

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“…Inflammatory mediators acting on their cell membrane receptors trigger intracellular mechanisms can regulate both focal adhesions and the cytoskeleton, initiating second messenger cascades, such as the ERK and the PKC pathways, that lead to pain. 3,12,17,20,32,35,46 The increased expression of integrin subunits a few days after a painful facet capsule injury (Figure 4) points to possible interactions between sustained pain signaling in nociceptors and regulation of integrins in those neurons. Although these studies support an emerging schema for integrin-dependent mechanically-induced facet joint pain, work is needed to fully characterize the temporal expression of different integrin subunits in the peripheral terminal of primary afferents in response to tissue injury.…”

Section: Discussionmentioning

confidence: 99%

“…14,46 Functionally blocking or knocking down certain integrin subunits, such as the integrin subunit 1, has been shown to prevent the pain induced by NGF or PGE 2 14,46 (Figure 1). Activation of neuronal 1 integrins in inflammatory pain may occur via direct regulation by NGF, 46,58,68 or interactions with the activated PGE 2 or NGF receptors through intracellular signaling cascades 15,17,46 (Figure 1). …”

Section: Introductionmentioning

confidence: 99%

A Nociceptive Role for Integrin Signaling in Pain After Mechanical Injury to the Spinal Facet Capsular Ligament

2017

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Integrins modulate chemically-induced nociception in a variety of inflammatory and neuropathic pain models. Yet, the role of integrins in mechanically-induced pain remains undefined, despite its well-known involvement in cell adhesion and mechanotransduction. Excessive spinal facet capsular ligament stretch is a common injury that induces morphological and functional changes in its innervating afferent neurons and can lead to pain. However, the local mechanisms underlying the translation from tissue deformation to pain signaling are unclear, impeding effective treatment. Therefore, the involvement of the integrin subunit β1 in pain signaling from facet injury was investigated in complementary in vivo and in vitro studies. An anatomical study in the rat identified expression of the integrin subunit β1 in dorsal root ganglion (DRG) neurons innervating the facet, with greater expression in peptidergic than non-peptidergic DRG neurons. Painful facet capsule stretch in the rat upregulated the integrin subunit β1 in small- and medium-diameter DRG neurons at day 7. Inhibiting the α2β1 integrin in a DRG-collagen culture prior to its stretch injury prevented strain-induced increases in axonal substance P (SP) in a dose-dependent manner. Together, these findings suggest that integrin subunit 1-dependent pathways may contribute to SP-mediated pain from mechanical injury of the facet capsular ligament.

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Plasma Membrane Mechanisms in a Preclinical Rat Model of Chronic Pain

Cited by 29 publications

References 36 publications

Marked sexual dimorphism in 5-HT 1 receptors mediating pronociceptive effects of sumatriptan

Marked sexual dimorphism in 5-HT 1 receptors mediating pronociceptive effects of sumatriptan

Adenosine-A1 receptor agonist induced hyperalgesic priming type II

A Nociceptive Role for Integrin Signaling in Pain After Mechanical Injury to the Spinal Facet Capsular Ligament

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