Nerve growth factor (NGF) has emerged as a key driver of pain perception in several chronic pain conditions, including osteoarthritis (OA), and plays an important role in the generation and survival of neurons. Although anti-NGF antibodies improve pain control and physical function in patients with clinical chronic pain conditions, anti-NGF IgGs are associated with safety concerns such as effects on fetal and postnatal development and the risk of rapidly progressive osteoarthritis. To overcome these drawbacks, we generated a novel anti-NGF PEGylated Fab' antibody. The anti-NGF PEGylated Fab' showed specific binding to and biological inhibitory activity against NGF, and analgesic effects in adjuvant-induced arthritis model mice in a similar manner to an anti-NGF IgG. In collagen-induced arthritis model mice, the anti-NGF PEGylated Fab' showed higher accumulation in inflamed foot pads than the anti-NGF IgG. In pregnant rats and non-human primates, the anti-NGF PEGylated Fab' was undetectable in fetuses, while the anti-NGF IgG was detected and caused abnormal postnatal development. The PEGylated Fab' and IgG also differed in their ability to form immune complexes in vitro. Additionally, while both PEGylated Fab' and IgG showed analgesic effects in sodium monoiodoacetate-induced arthritic model rats, their effects on edema were surprisingly quite different. While the anti-NGF IgG promoted edema over time, the anti-NGF PEGylated Fab' did not. The anti-NGF PEGylated Fab' (ASP6294) may thus be a potential therapeutic candidate with lower risk of adverse effects for various diseases in which NGF is involved such as OA and chronic back pain.

The reserpine-induced myalgia (RIM) rat manifests fibromyalgia-like chronic pain symptoms. The present study explored the pathophysiology underlying the pain symptoms in the RIM rat and the chronic constriction injury (CCI) rat, an animal model of neuropathic pain as a reference. Nerve tissue samples were collected from the nociception-tested animals for pathological examinations. Additionally, the therapeutic efficacy of a sodium channel blocker mexiletine was assessed in both rats. A slight vacuolization in the substantia nigra (SN) occurred in some of the RIM rats without any other histopathological changes in the brain or peripheral neurons. All the RIM rats, with or without vacuolization, showed hypersensitivity to tactile, muscle pressure, and cold stimuli. In the CCI rat, neurodegenerative changes were apparent in the sciatic nerve and the spinal cord only. CCI rats displayed muscle hyperalgesia in addition to tactile and cold allodynia. Pharmacotherapy with mexiletine did not attenuate the pain in the RIM rat, although it was effective in the CCI rat. Taken together, it is not likely that pain symptoms in RIM rats are caused by degenerative changes at the level of primary afferents and spinal cord, as is the case for CCI rats. The significance of the vacuolization in the SN is less clear at present because of the minor extent of the change and the lack of correlation with nociceptive sensitivity. The pain symptoms in RIM rats could be associated with dysfunction of biogenic amines-mediated CNS pain control even without apparent pathologies in the nervous system.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are now understood to fall into one of two agent classes in clinical use. Traditional NSAIDs inhibit both cyclooxygenases-1 and 2 (COX-1, 2), which act as key enzymes catalyzing the same reaction in the production of prostaglandins (PGs), while the second class of NSAIDs selectively inhibit COX-2. Inhibition of the inducible COX-2 isoform is believed to be responsible for the therapeutic effects of NSAIDs, such as anti-inflammatory, analgesic, and antipyretic effects, while COX-1 inhibition results in side-effects on the gastrointestinal (GI) system. In the present study, however, we changed this notion that inhibiting only COX-1 causes adverse effects. We discovered FK881, a specific COX-1 inhibitor which exhibits a 650-fold ratio for human whole blood COX-1/COX-2 and rats in vivo. In rats, FK881 dose dependently inhibited carrageenan-induced paw edema (ED30: 22 mg/kg; diclofenac ED30: 3.6 mg/kg, rofecoxib ED30: 26 mg/kg) and paw swelling associated with adjuvant arthritis (ED50: 17 mg/kg; diclofenac ED50: 1.4 mg/kg, rofecoxib ED50: 1.8 mg/kg). Further, FK881 dose dependently inhibited acetic acid-induced writhing in mice (ED50: 19 mg/kg; diclofenac ED50: 14 mg/kg, rofecoxib ED50: >100mg/kg) and adjuvant arthritis hyperalgesia in rats (ED50: 1.8 mg/kg; diclofenac ED50: 1.0mg/kg, rofecoxib ED50: 0.8mg/kg). However, unlike traditional NSAIDs, GI tolerability was improved, although the antipyretic effect of FK881 was weak (NOEL: >320 mg/kg; diclofenac NOEL: <1mg/kg, rofecoxib NOEL: 100 mg/kg). These results suggest that FK881 may be useful in treating symptoms of rheumatoid arthritis and osteoarthritis.

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.doi.org/10.1254/jphs.10319FP].

European Journal of Pain SupplementsVolume 5, Issue S1 p. 35-35 T170 PATHOPHYSIOLOGY OF FIBROMYALGIA-LIKE CHRONIC PAIN IN THE RESERPINE-INDUCED MYALGIA RAT: COMPARISON WITH NEUROPATHIC- AND OSTEOARTHRITIS-ASSOCIATED PAIN MODELS M. Takahashi, M. Takahashi Department of Pain Research, Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., TsukubaSearch for more papers by this authorY. Nagakura, Y. Nagakura Department of Pain Research, Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., TsukubaSearch for more papers by this authorT. Noto, T. Noto Drug Safety Research Labs., Drug Discovery Research, Astellas Pharma Inc., Kashima, JapanSearch for more papers by this authorT. Sekizawa, T. Sekizawa Department of Pain Research, Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., TsukubaSearch for more papers by this authorT. Oe, T. Oe Department of Pain Research, Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., TsukubaSearch for more papers by this authorE. Yoshimi, E. Yoshimi Department of Pain Research, Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., TsukubaSearch for more papers by this authorK. Tamaki, K. Tamaki Department of Pain Research, Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., TsukubaSearch for more papers by this authorH. Ito, H. Ito Department of Pain Research, Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., TsukubaSearch for more papers by this authorY. Shimizu, Y. Shimizu Department of Pain Research, Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., TsukubaSearch for more papers by this author M. Takahashi, M. Takahashi Department of Pain Research, Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., TsukubaSearch for more papers by this authorY. Nagakura, Y. Nagakura Department of Pain Research, Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., TsukubaSearch for more papers by this authorT. Noto, T. Noto Drug Safety Research Labs., Drug Discovery Research, Astellas Pharma Inc., Kashima, JapanSearch for more papers by this authorT. Sekizawa, T. Sekizawa Department of Pain Research, Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., TsukubaSearch for more papers by this authorT. Oe, T. Oe Department of Pain Research, Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., TsukubaSearch for more papers by this authorE. Yoshimi, E. Yoshimi Department of Pain Research, Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., TsukubaSearch for more papers by this authorK. Tamaki, K. Tamaki Department of Pain Research, Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., TsukubaSearch for more papers by this authorH. Ito, H. Ito Department of Pain Research, Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., TsukubaSearch for more papers by this authorY. Shimizu, Y. Shimizu Department of Pain Research, Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., TsukubaSearch for more papers by this author First published: 30 January 2012 https://doi.org/10.1016/S1754-3207(11)70115-8Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume5, IssueS1September 2011Pages 35-35 RelatedInformation

To assess the pharmacological profile of AS1892802, a novel and selective Rho kinase (ROCK) inhibitor, we examined the effects of repeated dosing with AS1892802 on models of monoiodoacetate-induced arthritis and streptozotocin-induced neuropathy. Although single dosing of AS1892802 exerted a short-acting, moderate analgesic effect, repeated dosing exhibited a long-lasting and more potent analgesic effect in both models. Furthermore, the analgesic effect was sustained for seven days after the last administration. These results suggest that peripheral ROCK plays a crucial role in chronic pain maintenance and that AS1892802 may be useful in treating chronic pain.

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 AS1892802 [1-[(1S)-2-hydroxy-1-phenylethyl]-3-[4-(pyridin-4-yl)phenyl]urea], 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.