Despite the high incidence of neuropathic and inflammatory pain worldwide, effective drugs with few side effects are currently unavailable for the treatment of chronic pain. Recently, researchers have proposed that inhibitors of purinergic chemical transmission, which plays a key role in the pathological pain response, may allow for targeted treatment of pathological neuropathic and inflammatory pain. However, such therapeutic analgesic agents have yet to be developed. In the present study, we demonstrated that clodronate, a first-generation bisphosphonate with comparatively fewer side effects than traditional treatments, significantly attenuates neuropathic and inflammatory pain unrelated to bone abnormalities via inhibition of vesicular nucleotide transporter (VNUT), a key molecule for the initiation of purinergic chemical transmission. In vitro analyses indicated that clodronate inhibits VNUT at a halfmaximal inhibitory concentration of 15.6 nM without affecting other vesicular neurotransmitter transporters, acting as an allosteric modulator through competition with Cl − . A low concentration of clodronate impaired vesicular ATP release from neurons, microglia, and immune cells. In vivo analyses revealed that clodronate is more effective than other therapeutic agents in attenuating neuropathic and inflammatory pain, as well as the accompanying inflammation, in wild-type but not VNUT −/− mice, without affecting basal nociception. These findings indicate that clodronate may represent a unique treatment strategy for chronic neuropathic and inflammatory pain via inhibition of vesicular ATP release. vesicular nucleotide transporter | purinergic chemical transmission | analgesic effect | antiinflammatory effect | clodronate

About 60-85% of total phosphorus (P) in cereal crops is finally allocated to the seeds, which is required for seed development, germination, and early growth. However, little is known on the molecular mechanisms underlying P allocation to the seeds. Here, we found that two members (OsPHO1;1 and OsPHO1;2) belonging to PHO1 gene family, are involved in the distribution of P to the seeds in rice. Both OsPHO1;1 and OsPHO1;2 were localized to the plasma membrane and showed influx transport activities for inorganic phosphate. At the reproductive stage, both OsPHO1;1 and OsPHO1;2 showed higher expression in the node I, the uppermost node connecting to panicle. OsPHO1;1 was mainly localized at the phloem region of diffuse vascular bundles of node I, while OsPHO1;2 was expressed in the xylem parenchyma cells of the enlarged vascular bundles. In addition, they were also expressed in the ovular vascular trace, the outer layer of the inner integument (OsPHO1;1) and the nucellar epidermis (OsPHO1;2) of caryopsis. Knockout of OsPHO1;2 as well as OsPHO1;1 with less extent decreased the distribution of P to the seed, resulting in decreased seed size and delayed germination. Taken together, OsPHO1;2 expressed in node I is responsible for unloading of P from the xylem of enlarged vascular bundles, while OsPHO1;1 is involved in reloading P into phloem of diffuse vascular bundles for subsequent allocation of P to the seeds. Furthermore, OsPHO1;1 and OsPHO1;2 expressed in the caryopsis are important for delivering of P from the maternal tissues to the filial tissues for seed development.