Potent analgesic effects of a store-operated calcium channel inhibitor

Abstract

Chronic pain often accompanies immune responses and immune cells are known to be involved in chronic pain. Store-operated calcium (SOC) channels are calcium-selective cation channels and play an important role in the immune system. YM-58483, a potent SOC channel inhibitor, has been shown to inhibit cytokine production from immune cells and attenuate antigen-induced hypersensitivity reactions. Here, we report that YM-58483 has analgesic actions in chronic pain and produces antinociceptive effects in acute pain and prevents the development of chronic pain in mice. Oral administration of 10 mg/kg or 30 mg/kg YM-58483 dramatically attenuated Complete Freund's adjuvant (CFA)-induced thermal hyperalgesia and prevented the development of thermal and mechanical hypersensitivity in a dose-dependent manner. Analgesic effects were observed when YM-58483 administered systemically, intrathecally, and also intraplantarly. YM-58483 decreased spared nerve injury (SNI)-induced thermal and mechanical hypersensitivity and prevented the development of SNI-induced pain hypersensitivity. Pretreatment with YM-58483 strongly reduced both the first and second phases of formalin-induced spontaneous nocifensive behavior dose-dependently. YM-58483 produced antinociception in acute pain induced by heat or chemical or mechanical stimuli at the dose of 30 mg/kg. YM-58483 diminished CFA-induced paw edema, and reduced production of TNF-α, IL-1β and PGE2 in the CFA-injected paw. In vitro, SOC entry in nociceptors was more robust than in nonnociceptors, and the inhibition of SOC entry by YM-58483 in nociceptors was much greater than in non-nociceptors. Our findings indicate that YM-58483 is a potent analgesic and suggest that SOC channel inhibitors may represent a novel class of therapeutics for pain.

A store‐operated calcium channel inhibitor attenuates collagen‐induced arthritis

“…Various pro‐inflammatory cytokines, such as TNF‐α, IL‐1β and IL‐6, are present in the joints of RA patients and numerous studies have provided evidence that these pro‐inflammatory cytokines play an important role in the development of arthritis and arthritis‐induced pain (Constandil et al ., ; Segond von Banchet et al ., ). We have previously shown that YM‐58483 inhibits the production of TNF‐α and IL‐1β in mice with CFA‐induced inflammation of the paw (Gao et al ., ). To better understand the peripheral mechanisms that contribute to the ability of YM‐58483 to prevent or reduce the effects of CIA, we measured levels of TNFα, IL‐1β and IL‐6 in the paws of normal and CIA mice.…”

“…Pain is one of the first and most disabling manifestations in patients with arthritis (Zatarain and Strand, ). Our previous study demonstrated that YM‐58483 has strong analgesic effects (Gao et al ., ), so we wanted to determine whether these analgesic effects extended to arthritic pain. CIA mice developed mechanical allodynia on day 21 and thermal hyperalgesia on day 28 after the first injection of collagen (Figure A); prior to the onset of most other symptoms of CIA.…”

“…However, there is no direct in vivo evidence to support this notion. Our previous study demonstrated that YM‐58483 strongly reduces CFA‐induced inflammation (Gao et al ., ) and we hypothesized that YM‐58483 would also reduce inflammation in CIA mice. Consistent with this hypothesis, we found that treatment with YM‐58483 significantly decreased joint inflammation in CIA mice by reducing synovial inflammation, synovial hyperplasia and bone erosion.…”

“…Previous studies have also shown that YM‐58483 inhibits red blood cell‐induced delayed‐type hypersensitivity responses and reduces antigen‐induced bronchial asthma (Yoshino et al ., ; Ohga et al ., ). Consistent with these peripheral actions, we have recently demonstrated that YM‐58483 reduces oedema and local levels of TNF‐α and IL‐1β in an inflammatory pain model (Gao et al ., ).…”

Norisoboldine attenuates inflammatory pain via the adenosine A1 receptor

“…Paw oedema of the injected paw was expressed by percentage change in paw volume, and the paw volume was determined by plethysmometry (volume displacement) as previously described (Gao et al, 2013). Paw oedema of the injected paw was expressed by percentage change in paw volume, and the paw volume was determined by plethysmometry (volume displacement) as previously described (Gao et al, 2013).…”