A new model of nerve injury in the rat reveals a role of Regulator of G protein Signaling 4 in tactile hypersensitivity

Taccola, Giuliano; Damblon, Jonathan; Dingu, Nejada; Ballarin, Beatrice; Steyaert, Arnaud; Rieux, Anne des; Forget, Patrice; Hermans, Emmanuel; Bosier, Barbara; Deumens, Ronald

doi:10.1016/j.expneurol.2016.09.008

Cited by 14 publications

(18 citation statements)

References 53 publications

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“…Furthermore, several studies have demonstrated a role of RGS4 in functional responses to opioid receptor agonists (Georgoussi et al, 2006;Ajit et al, 2007;Han et al, 2010). RGS4 is expressed in many structures involved in the transmission and maintenance of chronic pain, including the dorsal horn of the spinal cord, the periaqueductal gray (PAG), the thalamus, and the basal ganglia (Ni et al, 1999;Gold et al, 2003;Terzi et al, 2009;Taccola et al, 2016). Based on the distribution pattern of RGS4 and its potent modulatory role in signal transduction events triggered by G␣ and G␤␥ proteins, we expect that changes in RGS4 activity may affect functional responses of several GPCRs and ion channels throughout the pain matrix.…”

Section: Introductionmentioning

confidence: 99%

“…Understanding the functional significance of RGS4 in the development and maintenance of chronic pain states may contribute essential knowledge to the cellular determinants of sensory hypersensitivity and pain chronicity. Recent reports propose that intrathecal application of RGS4 inhibitors in rodents alleviates mechanical allodynia and pain-like behaviors (Bosier et al, 2015;Yoon et al, 2015;Taccola et al, 2016). Here, we apply constitutive and conditional knock-out models to understand the role of RGS4 in the induction, intensity, and maintenance of chronic pain symptoms.…”

Section: Introductionmentioning

confidence: 99%

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RGS4 Maintains Chronic Pain Symptoms in Rodent Models

et al. 2019

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Regulator of G-protein signaling 4 (RGS4) is a potent modulator of G-protein-coupled receptor signal transduction that is expressed throughout the pain matrix. Here, we use genetic mouse models to demonstrate a role of RGS4 in the maintenance of chronic pain states in male and female mice. Using paradigms of peripheral inflammation and nerve injury, we show that the prevention of RGS4 action leads to recovery from mechanical and cold allodynia and increases the motivation for wheel running. Similarly, RGS4KO eliminates the duration of nocifensive behavior in the second phase of the formalin assay. Using the Complete Freud's Adjuvant (CFA) model of hindpaw inflammation we also demonstrate that downregulation of RGS4 in the adult ventral posterolateral thalamic nuclei promotes recovery from mechanical and cold allodynia. RNA sequencing analysis of thalamus (THL) from RGS4WT and RGS4KO mice points to many signal transduction modulators and transcription factors that are uniquely regulated in CFA-treated RGS4WT cohorts. Ingenuity pathway analysis suggests that several components of glutamatergic signaling are differentially affected by CFA treatment between RGS4WT and RGS4KO groups. Notably, Western blot analysis shows increased expression of metabotropic glutamate receptor 2 in THL synaptosomes of RGS4KO mice at time points at which they recover from mechanical allodynia. Overall, our study provides information on a novel intracellular pathway that contributes to the maintenance of chronic pain states and points to RGS4 as a potential therapeutic target.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

RGS4 Maintains Chronic Pain Symptoms in Rodent Models

et al. 2019

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“…A report also indicates increases in RGS3 mRNA in the dorsal horn of the lumbar spinal cord after sciatic nerve ligation, although RGS4 levels decrease several days later; these effects may involve astrocyte RGS proteins (Doyen et al, 2017). In support of a role for up-regulated RGS4 (and RGS3) in reducing the effectiveness of morphine, use of the inhibitor CCG-63802 (Figure 2; Blazer et al, 2010) to prevent RGS4 action attenuates hyperalgesia following nerve injury (Bosier et al, 2015;Taccola et al, 2016). This attenuation can be attributed to the rescue of tonically active endogenous antinociception systems, such as the enkephalins, although in one study using this inhibitor (Bosier et al, 2015) endogenous cannabinoids rather than opioid endogenous opioids were implicated.…”

Section: R4 Familymentioning

confidence: 96%

“…RGS proteins are variously expressed throughout the body including pain pathways in the central nervous system (CNS) where expression overlaps with MOR expression, particularly for RGS4 and the splice variant of RGS9, RGS9-2 (Gold et al, 1997;Peckys and Landwehrmeyer, 1999;Grafstein-Dunn et al, 2001;Traynor and Neubig, 2005). For example, the small RGS4 protein is expressed in many structures involved in the transmission and maintenance of pain, including the dorsal horn of the spinal cord, the periaqueductal gray (PAG), the thalamus, and the basal ganglia (Ni et al, 1999;Gold et al, 2003;Terzi et al, 2009;Taccola et al, 2016).…”

Section: Rgs Proteinsmentioning

confidence: 99%

“…A more important role for RGS4 might be in chronic pain states, where RGS4 expression is dynamically regulated. For example, following sciatic nerve injury in the rat there is an upregulation of RGS4 mRNA expression in the dorsal horn of the spinal cord, with no change in the mRNA of other RGS proteins measured (RGS6, 7, 8, 9, 11, 12, 14, 17, 19;Garnier et al, 2003;Bosier et al, 2015;Taccola et al, 2016). At the same time rats become hypersensitive to noxious stimuli and the potency of MOR agonists decreases.…”

Section: R4 Familymentioning

confidence: 99%

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Regulator of G-Protein Signaling (RGS) Protein Modulation of Opioid Receptor Signaling as a Potential Target for Pain Management

Senese

Kandasamy

Kochan

et al. 2020

Front. Mol. Neurosci.

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Opioid drugs are the gold standard for the management of pain, but their use is severely limited by dangerous and unpleasant side effects. All clinically available opioid analgesics bind to and activate the mu-opioid receptor (MOR), a heterotrimeric G-protein-coupled receptor, to produce analgesia. The activity of these receptors is modulated by a family of intracellular RGS proteins or regulators of G-protein signaling proteins, characterized by the presence of a conserved RGS Homology (RH) domain. These proteins act as negative regulators of G-protein signaling by serving as GTPase accelerating proteins or GAPS to switch off signaling by both the Gα and βγ subunits of heterotrimeric G-proteins. Consequently, knockdown or knockout of RGS protein activity enhances signaling downstream of MOR. In this review we discuss current knowledge of how this activity, across the different families of RGS proteins, modulates MOR activity, as well as activity of other members of the opioid receptor family, and so pain and analgesia in animal models, with particular emphasis on RGS4 and RGS9 families. We discuss inhibition of RGS proteins with small molecule inhibitors that bind to sensitive cysteine moieties in the RH domain and the potential for targeting this family of intracellular proteins as adjuncts to provide an opioid sparing effect or as standalone analgesics by promoting the activity of endogenous opioid peptides. Overall, we conclude that RGS proteins may be a novel drug target to provide analgesia with reduced opioid-like side effects, but that much basic work is needed to define the roles for specific RGS proteins, particularly in chronic pain, as well as a need to develop newer inhibitors.

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Astrocyte reactivity in spinal cord and functional impairment after tendon injury in rats

Mendes

Sousa

França

et al. 2021

Heliyon

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Astrocyte reactivity in the spinal cord may occur after peripheral neural damage. However, there is no data to report such reactivity after Achilles tendon injury. We investigate whether changes occur in the spinal cord, mechanical sensitivity and gait in two phases of repair after Achilles tendon injury. Wistar rats were divided into groups: control (CTRL, without rupture), 2 days post-injury (RUP2) and 21 days post-injury (RUP21). Functional and mechanical sensitivity tests were performed at 2 and 21 days post-injury (dpi). The spinal cords were processed, cryosectioned and activated astrocytes were immunostained by GFAP at 21 dpi. Astrocyte reactivity was observed in the L5 segment of the spinal cord with predominance in the white matter regions and decrease in the mechanical threshold of the ipsilateral paw only in RUP2. However, there was gait impairment in both RUP2 and RUP21. We conclude that during the acute phase of Achilles tendon repairment, there was astrocyte reactivity in the spinal cord and impairment of mechanical sensitivity and gait, whereas in the chronic phase only gait remains compromised.

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A new model of nerve injury in the rat reveals a role of Regulator of G protein Signaling 4 in tactile hypersensitivity

Cited by 14 publications

References 53 publications

RGS4 Maintains Chronic Pain Symptoms in Rodent Models

RGS4 Maintains Chronic Pain Symptoms in Rodent Models

Regulator of G-Protein Signaling (RGS) Protein Modulation of Opioid Receptor Signaling as a Potential Target for Pain Management

Astrocyte reactivity in spinal cord and functional impairment after tendon injury in rats

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