Rho-kinase inhibitor, Y-27632, has an antinociceptive effect in mice

Büyükafşar, Kansu; Yalçın, İpek; Kurt, Akif Hakan; Tiftik, Rukiye Nalan; Şahan-Fırat, Seyhan; Aksu, Fazilet

doi:10.1016/j.ejphar.2006.04.042

Cited by 34 publications

(20 citation statements)

References 20 publications

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“…Some studies have investigated the relationship between ROCK and chondrocytes (9 -11). Moreover, Rho signal transduction has been reported to be involved in initiation of neuropathic pain (12) and ROCK inhibitors have also been reported to act as analgesics: Y27632 had antihyperalgesic effects in mice (13) and H-1152, a commercially available ROCK inhibitor, suppressed nociceptive and neurogenic pain (14). However, efficacy or the therapeutic effect of ROCK inhibitors in in vivo models of cartilage degeneration or in clinical settings has not been reported.…”

Section: Introductionmentioning

confidence: 99%

Alleviating Effects of AS1892802, a Rho Kinase Inhibitor, on Osteoarthritic Disorders in Rodents

et al. 2011

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Abstract. The effects of AS1892802, a selective Rho-associated coiled coil kinase (ROCK) inhibitor, on knee cartilage damage and pain behavior were examined in a rat model of osteoarthritis (OA). Monoiodoacetate (MIA) was intraarticularly injected into the right knee joints of rats. ROCK I and II mRNA levels increased in knee joints of MIA-injected rats. Our newly synthesized ROCK inhibitor, AS1892802, was injected into the ipsilateral knee or administered p.o. for 3 weeks. The compound dose-dependently and significantly inhibited of cartilage damage in the tibial plateau in a dose-dependent manner and decreased the weight distribution deficit associated with MIA injection. In addition, the compound also inhibited bradykinin induced pain responses in normal rats. In vitro, the compound could induce chondrocyte differentiation in a chondrogenic cell line and significantly inhibited IL-1β-or bradykinin-induced prostaglandin E 2 production in a synovial cell line. AS1892802 prevents cartilage damage induced by MIA and has analgesic effects in rat pain models, suggesting that AS1892802 may be clinically useful for the treatment of OA.[Supplementary Figure: available only at http://dx

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Section: Introductionmentioning

confidence: 99%

Alleviating Effects of AS1892802, a Rho Kinase Inhibitor, on Osteoarthritic Disorders in Rodents

et al. 2011

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“…In addition, a recent paper showed that the RhoA/ROCK pathway is also involved in thermal hyperalgesia in diabetic mice [49] . Furthermore, the activation of RhoA and ROCK is related to spinal nociceptive transmission [14,15,47,48] , and the inhibition of ROCK attenuates inflammatory and neuropathic pain [13,47] , whereas the activation of RhoA by the injection of lysophosphatidic acid induces hyperalgesia and allodynia [13] . The injection of H-1152, a ROCK inhibitor, significantly reduced the Phase II pain behavior resulting from the formalin injection by attenuating the phosphorylation of MARCKS in the superficial dorsal horn of the spinal cord [14] .…”

Section: Rhoa Activity Is Increased In the Spinal Cord Of Dlc2mentioning

confidence: 99%

“…A dramatic increase in RhoA activity was observed in the ipsilateral spinal cord 30 min after the formalin injection. It is well known that the activation of RhoA and its effector ROCK is related to spinal nociceptive transmission [14,15,47,48] and that the inhibition of ROCK attenuates inflammatory and neuropathic pain [13,47] . In addition, a recent paper showed that the RhoA/ROCK pathway is also involved in thermal hyperalgesia in diabetic mice [49] .…”

Section: Rhoa Activity Is Increased In the Spinal Cord Of Dlc2mentioning

confidence: 99%

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The RhoA GTPase-Activating Protein DLC2 Modulates RhoA Activity and Hyperalgesia to Noxious Thermal and Inflammatory Stimuli

Chan¹,

Chung

Ng³

et al. 2012

Neurosignals

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Deleted in liver cancer 2 (DLC2) is a novel Rho GTPase-activating protein that regulates RhoA activity. DLC2 is ubiquitously expressed in most tissues, including the brain, spinal cord and peripheral nerves, and is thought to be involved in actin cytoskeletal reorganization. Unlike DLC1-deficient mice, DLC2-deficient mice (DLC2^–/–) are viable and without gross anatomical abnormalities. Interestingly, DLC2^–/– mice exhibit hyperalgesia to noxious thermal stimuli and inflammation-inducing chemicals, such as formalin and acetic acid. There was no difference in the structure or morphology of cutaneous or sural nerves between DLC2^+/+ and DLC2^–/– mice. However, sensory nerve conduction velocity in DLC2^–/– mice was significantly higher than that in DLC2^+/+ mice, whereas motor nerve conduction velocity was not affected. After formalin injection, DLC2^–/– mice showed increased RhoA activity in the spinal cord and an increased number of phosphorylated ERK1/2-positive cells. The inflammatory hyperalgesia in DLC2^–/– mice appeared to be mediated through the activation of RhoA and ERK1/2. Taken together, DLC2 plays a key role in pain modulation during inflammation by suppressing the activation of RhoA and ERK to prevent an exaggerated pain response, and DLC2^–/– mice provide a valuable tool for further understanding the regulation of inflammatory pain.

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“…Although an analgesic effect has been demonstrated by intraperitoneal injection of the ROCK inhibitor Y-27632 [(ϩ)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride] in the mouse hot plate test and acetic acid-induced writhing test (Bü yü kafşar et al, 2006), the effect of ROCK inhibitors in an osteoarthritis model has not yet been investigated.…”

Section: Introductionmentioning

confidence: 99%

Antinociceptive Effects of AS1892802, a Novel Rho Kinase Inhibitor, in Rat Models of Inflammatory and Noninflammatory Arthritis

Yoshimi

Kumakura²,

Hatori³

et al. 2010

J Pharmacol Exp Ther

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Rho kinase (ROCK) is involved in various physiological functions, including cell motility, vasoconstriction, and neurite extension. Although a functional role of ROCK in nociception in the central nervous tissue has been reported in neuropathy, the peripheral function of this protein in hyperalgesia is not known. In this study, antinociceptive effects of, a novel and highly selective ROCK inhibitor, were investigated in two rat models of arthritis. Orally administered AS1892802 exhibited potent antinociceptive effect in both an adjuvant-induced arthritis (AIA) model (inflammatory arthritis model) and a monoiodoacetate-induced arthritis (MIA) model (noninflammatory arthritis model), with an ED 50 of 0.15 mg/kg (MIA model). Fasudil, a ROCK inhibitor, and tramadol were also effective in both models; however, diclofenac was effective only in the AIA model. The onset of antinociceptive effect of AS1892802 was as fast as those of tramadol and diclofenac. AS1892802 did not induce gastric irritation or abnormal behavior. Because AS1892802 rarely penetrates the central nervous tissue and is also effective by intra-articular administration, it seemed to function peripherally. These results suggest that AS1892802 has an attractive analgesic profile for the treatment of severe osteoarthritis pain.

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Rho-kinase inhibitor, Y-27632, has an antinociceptive effect in mice

Cited by 34 publications

References 20 publications

Alleviating Effects of AS1892802, a Rho Kinase Inhibitor, on Osteoarthritic Disorders in Rodents

Alleviating Effects of AS1892802, a Rho Kinase Inhibitor, on Osteoarthritic Disorders in Rodents

The RhoA GTPase-Activating Protein DLC2 Modulates RhoA Activity and Hyperalgesia to Noxious Thermal and Inflammatory Stimuli

Antinociceptive Effects of AS1892802, a Novel Rho Kinase Inhibitor, in Rat Models of Inflammatory and Noninflammatory Arthritis

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