Nobuaki Takeshita

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

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 ED50 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.

A Vacuolar ATPase Inhibitor, FR167356, Prevents Bone Resorption in Ovariectomized Rats With High Potency and Specificity: Potential for Clinical Application†

FR167356, a novel inhibitor of vacuolar ATPase, has high potency against osteoclast V‐ATPase and low potency against lysosomal V‐ATPase. FR167356 is the first compound of this nature to be tested. It has the potential to be useful for clinical application.

Efficacy of drugs with different mechanisms of action in relieving spontaneous pain at rest and during movement in a rat model of osteoarthritis.

Patients with osteoarthritis (OA) suffer from joint pain aggravated by movement, which affect their quality of life. In the present study, a weight bearing paradigm for pain at rest and a gait paradigm for pain during movement were tested in rats with unilateral knee arthritis induced by an intra-articular injection of sodium monoiodoacetate (MIA). At week 3 after MIA (1mg/knee) injection, animals developed pain-associated, right-left imbalances of weight distribution (weight bearing) or foot print parameters (gait). Diclofenac, at doses up to 30 mg/kg orally (p.o.), did not have a significant effect on either paradigm. Morphine rectified the weight bearing and gait imbalances at 1 and 3mg/kg subcutaneously, respectively. The weak opioid and serotonin/norepinephrine reuptake inhibitor (SNRI) tramadol also significantly corrected the indices at 10mg/kg (weight bearing) and 100mg/kg p.o. (gait). The SNRI duloxetine at 30 mg/kg p.o. corrected the weight bearing imbalance but not gait imbalance. We assessed the effect of different drugs on pain-induced disturbances in weight distribution and gait in MIA-induced arthritic rats. Analgesic drugs, each with different mechanisms of action, were less effective in rectifying the imbalance in gait than that in weight distribution. The assessment of the effect of analgesics on not only rest pain but pain during movement is valuable for the comprehensive examination of their therapeutic efficacies in OA.

Nociceptive cortical responses during capsaicin-induced tactile allodynia in mice with spinal dorsal column lesioning

We investigated nociceptive cortical responses using transcranial flavoprotein fluorescence imaging in anesthetized mice with capsaicin-induced allodynia. Tactile stimuli applied to the hindpaw produced fluorescence increases in the contralateral somatosensory cortex of naïve mice. Lesioning of the ipsilateral dorsal column in the spinal cord abolished most of the cortical responses. However, the responses to the same tactile stimuli appeared again after capsaicin was injected into the hindpaw. The capsaicin treatment reduced the thresholds of the hindpaw withdrawal responses. These findings strongly suggest that the responses to tactile stimuli in the lesioned mice after capsaicin injection represented nociceptive cortical responses.

Therapeutic effects of diclofenac, pregabalin, and duloxetine on disuse-induced chronic musculoskeletal pain in rats

The aim of this study was to clarify the mechanism of disuse-induced muscle hyperalgesia through the evaluation of the pharmacological behaviour of muscle hyperalgesia profiles in chronic post-cast pain (CPCP) rats with acute and chronic-phase mirror-image muscle hyperalgesia treated with diclofenac (NSAID), pregabalin (an inhibitor of Ca2+ channel α2δ), and duloxetine (SNRI). After 2 weeks of cast immobilization, the peak cross-sectional area and muscle wet weight of the ipsilateral soleus and gastrocnemius muscles decreased more significantly in CPCP rats than in untreated rats. Histological findings revealed disuse-induced muscle atrophy in CPCP rats. The blood biochemical parameters of CPCP rats in acute and chronic phases did not differ significantly from those of untreated rats. The diclofenac and pregabalin-treated groups exhibited no improvement in acute or chronic muscle hyperalgesia. In contrast, the duloxetine-treated group exhibited an improvement in acute muscle hyperalgesia, but showed no apparent effect on chronic muscle hyperalgesia on ipsilateral or contralateral sides. However, the chronic muscle hyperalgesia was reversed by intrathecal administration of DAMGO (a μ-opioid receptor agonist). The results suggest that chronic muscle hyperalgesia in CPCP rats did not result from an inflammatory mechanism, and there is only a low probability that it’s caused by a neuropathic mechanism.

AS1069562, the (+)-isomer of indeloxazine, exerts analgesic effects in rat models of nociceptive pain

Abstract Objectives: The (+)-isomer of indeloxazine AS1069562 has multiple pharmacological actions, such as serotonin (5-HIT) and norepinephrine (NE) reuptake inhibition and analgesic effects in animal models of neuropathic pain. Here, we investigated the analgesic effects of AS1069562 in rat models of inflammatory and noninflammatory nociceptive pain. Methods: Adjuvant-induced arthritis (AIA) and bradykinin-induced knee joint pain were used as rat models of inflammatory pain. The chronic phase of monoiodoacetate-induced arthritis (MIA) was used as a rat model of noninflammatory pain. Analgesic effects were evaluated by weight-bearing deficit in the AIA and MIA models and by pain response in the bradykinin-induced knee joint pain model. Results: In the AIA model and the bradykinin-induced knee joint pain model, AS1069562 significantly ameliorated the pain-related behavior of weight-bearing deficit and the pain response, respectively. AS1069562 also significantly improved the pain-related behavior of weight-bearing deficit in the chronic phase of the MIA model. Further, following monoiodoacetate injection, repeated administration of AS1069562 or duloxetine significantly improved weight-bearing deficit in the MIA model. Interestingly, the analgesic effect of AS1069562 was sustained for 24 hours after the last administration, although the plasma concentration of AS1069562 was reduced to undetectable levels. In contrast, the analgesic effect of duloxetine did not continue after treatment discontinuation. Discussion: AS1069562 exerts analgesic effects on inflammatory and noninflammatory nociceptive pain in rat models of arthritis pain, and repeated administration of AS1069562 exerts a more persistent analgesic effect on arthritis pain than duloxetine. These findings suggest that AS1069562 has an attractive analgesic profile for the treatment of nociceptive pain.