Minodronic acid, a third-generation bisphosphonate, antagonizes purinergic P2X2/3 receptor function and exerts an analgesic effect in pain models

Kakimoto, Shuichiro; Nagakura, Yukinori; Tamura, Shinzo; Watabiki, Tomonari; Shibasaki, Kumiko; Tanaka, Shohei; Mori, Masamichi; Sasamata, Masao; Okada, Masamichi

doi:10.1016/j.ejphar.2008.05.011

Cited by 35 publications

(27 citation statements)

References 17 publications

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“…In this study, significant analgesic effects of minodronate were seen in the tonic phase (phase 2) of formalin-induced acute inflammation, but not in the initial phase (phase 1) of acute pain. This result supports previous findings that minodronate decreases the duration of formalin-induced nociceptive behavior in mice (12). Minodronate shows antagonistic actions against the P2X2/3 receptor (12) which is specifically expressed on nociceptive sensory neurons and is considered to be involved in various pain states, such as inflammatory, neuropathic, and REFERENCES bisphosphonate, minodronate is also speculated to exert analgesic effects against chronic bone pain, including pain resulting from the acidic environment created by osteoclasts.…”

Section: Methodssupporting

confidence: 80%

“…This receptor is specifically expressed on nociceptive sensory neurons and is considered to be involved in various pain states such as inflammatory, neuropathic, and cancer pain (4,5). Previous reports have shown that minodronate decreases the duration of formalin-induced nociceptive behavior in mice in a dose-dependent manner (12). Acute pain can be divided into an initial acute phase (phase 1) and a prolonged tonic phase (phase 2).…”

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confidence: 99%

“…Recent reports have shown that bisphosphonates exert analgesic effects on bone pain by inhibiting bone resorption in patients with osteoporosis (1,2,9,10,13,15,16). Reports have shown that among bisphosphonates, only minodronate (a third-generation bisphosphonate) has antagonistic effects on the P2X2/3 receptor (12), and is thereby expected to show greater analgesic effects than the other bisphosphonates. This receptor is specifically expressed on nociceptive sensory neurons and is considered to be involved in various pain states such as inflammatory, neuropathic, and cancer pain (4,5).…”

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Analgesic effects of minodronate on formalin-induced acute inflammatory pain in rats

et al. 2013

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Minodronate is expected to produce greater analgesic effects than other bisphosphonates. However, there are no studies comparing bisphosphonate analgesic effects on formalin-induced acute inflammatory pain in rats. The purpose of the present study was to evaluate the analgesic effects of minodronate, morphine, and placebo. Four-month-old female Wistar rats were administered minodronate (50 mg/kg), morphine (10 mg/kg), or vehicle (n = 10 each) injections. Thirty minutes later, all rats were injected with formalin (right hind paw) to induce acute inflammatory pain. Paw licking and lifting as indicators of nociceptive pain responses were monitored from 0 to 5 min (phase 1; chemical-stimulation state) and then from 10 to 30 min (phase 2; spinal-sensitized state) after injection. The percentage of limb usage of the formalin-injected and the non-injected sides were measured in phases 1 and 2 by counting foot stamps. Minodronate significantly decreased nociceptive responses and increased limb usage compared with vehicle in phase 2 only (P < 0.05). Morphine significantly decreased nociceptive responses and increased limb usage compared with minodronate and vehicle in both phase 1 and 2 (P < 0.05). In conclusion, minodronate showed significant analgesic effects for formalin-induced acute pain in the spinal-sensitized state.

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Section: Methodssupporting

confidence: 80%

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confidence: 99%

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confidence: 99%

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Analgesic effects of minodronate on formalin-induced acute inflammatory pain in rats

et al. 2013

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“…Furthermore, an in vitro experiment showed the inhibitory effect of risedronate on axonal growth of neurite of pain-related DRG neurons from rat neonates 39) , indicating that a bisphosphonate itself can produce an analgesic effect by suppressing peripheral nerve function. Moreover, a third-generation of minodronic acid has been reported to have an analgesic effect by antagonizing purinergic P2X(2/3) receptor function 62) . One study showed that pa- tients treated with daily minodronate showed more pain relief measured on the visual analog scale 63) .…”

Section: Antiresorptive Agents: Bisphosphonate and Denosumabmentioning

confidence: 99%

Pathomechanisms and management of osteoporotic pain with no traumatic evidence

Orita

Inage

Suzuki

et al. 2017

Spine Surg Relat Res

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Abstract:Introduction: Osteoporosis is a pathological state with an unbalanced bone metabolism mainly caused by accelerated osteoporotic osteoclast activity due to a postmenopausal estrogen deficiency, and it causes some kinds of pain, which can be divided into two types: traumatic pain due to a fragility fracture from impaired rigidity, and pain derived from an osteoporotic pathology without evidence of fracture. We aimed to review the concepts of osteoporosis-related pain and its management.Methods: We reviewed clinical and basic articles on osteoporosis-related pain, especially with a focus on the mechanism of pain derived from an osteoporotic pathology (i.e., osteoporotic pain) and its pharmacological treatment.Results: Osteoporosis-related pain tends to be robust and acute if it is due to fracture or collapse, whereas pathologyrelated osteoporotic pain is vague and dull. Non-traumatic osteoporotic pain can originate from an undetectable microfracture or structural change such as muscle fatigue in kyphotic patients. Furthermore, basic studies have shown that the osteoporotic state itself is related to pain or hyperalgesia with increased pain-related neuropeptide expression or acid-sensing channels in the local tissue and nervous system. Traditional treatment for osteoporotic pain potentially prevents possible fracture-induced pain by increasing bone mineral density and affecting related mediators such as osteoclasts and osteoblasts. The most common agent for osteoporotic pain management is a bisphosphonate. Other non-osteoporotic analgesic agents such as celecoxib have also been reported to have a suppressive effect on osteoporotic pain.Conclusions: Osteoporotic pain has traumatic and non-traumatic factors. Anti-osteoporotic treatments are effective for osteoporotic pain, as they improve bone structure and the condition of the pain-related sensory nervous system. Physicians should always consider these matters when choosing a treatment strategy that would best benefit patients with osteoporotic pain.

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“…1). Interestingly, minodronate reportedly displays an ABRE-independent analgesic effect via its antagonism of the purinergic P2X 2/3 receptor (Kakimoto et al 2008), although such an analgesic effect has not been reported for other N-BPs. In addition, minodronate-related cases of ONJ are absent from the literature Okazaki et al 2011), and it apparently has no gastrointestinal adverse effects Okazaki et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Inflammatory and Necrotic Effects of Minodronate, a Nitrogen-Containing Bisphosphonate, in Mice

Kiyama

Okada

Tanaka

et al. 2013

Tohoku J. Exp. Med.

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Diseases involving enhanced bone-resorption (e.g., osteoporosis) are widely treated with bisphosphonates (BPs). BPs are of two types: the nitrogen-containing BPs (N-BPs) and the non-nitrogen-containing BPs (non-N-BPs). N-BPs have much stronger anti-bone-resorptive effects than non-N-BPs, and N-BPs can exert inflammatory and necrotic effects, including osteonecrosis of jawbones. Minodronate, an N-BP, was approved in 2009 in Japan for osteoporosis. Its anti-bone-resorptive effect is comparable to that of zoledronate, the N-BP with the strongest anti-bone-resorptive effect and the highest risk of side effects yet reported. Unlike other N-BPs, minodronate has an analgesic effect, and no serious side effects have been documented. Here, to examine whether minodronate lacks inflammatory and/or necrotic effects, we used mice (since the N-BPs tested so far induce such effects in mice with potencies that parallel those reported in humans). To facilitate comparison with previous studies, we gave a single systemic (intraperitoneal) or local (ear pinna) injection of minodronate (or another N-BP). We measured the systemic responses (weight of thoracic exudate, number of inflammatory cells in the peritoneal cavity, and spleen weight) or local responses (area of inflamed skin and incidence of necrosis). Anti-bone-resorptive effects were evaluated by X-ray analysis of tibias following intraperitoneal injection. Minodronate's anti-bone-resorptive effect and its inflammatory and necrotic effects were as great as, or greater than those of zoledronate. Moreover, in cultured human periodontal ligament cells, the cytotoxicity of minodronate was significantly greater than that of zoledronate. These results suggest that caution may be needed with minodronate in clinical use, as with other N-BPs.

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Minodronic acid, a third-generation bisphosphonate, antagonizes purinergic P2X2/3 receptor function and exerts an analgesic effect in pain models

Cited by 35 publications

References 17 publications

Analgesic effects of minodronate on formalin-induced acute inflammatory pain in rats

Analgesic effects of minodronate on formalin-induced acute inflammatory pain in rats

Pathomechanisms and management of osteoporotic pain with no traumatic evidence

Inflammatory and Necrotic Effects of Minodronate, a Nitrogen-Containing Bisphosphonate, in Mice

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