Antidepressants Inhibit P2X4 Receptor Function: a Possible Involvement in Neuropathic Pain Relief

K. Nagata1, Tamaki Imai1, Tomohiro Yamashita1, Makoto Tsuda1, Hidetoshi Tozaki‐Saitoh1, Kazuhide Inoue1
1Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812–8582, Japan

Tóm tắt

Background

Neuropathic pain is characterized by pain hypersensitivity to innocuous stimuli (tactile allodynia) that is nearly always resistant to known treatments such as non-steroidal anti-inflammatory drugs or even opioids. It has been reported that some antidepressants are effective for treating neuropathic pain. However, the underlying molecular mechanisms are not well understood. We have recently demonstrated that blocking P2X4 receptors in the spinal cord reverses tactile allodynia after peripheral nerve injury in rats, implying that P2X4 receptors are a key molecule in neuropathic pain. We investigated a possible role of antidepressants as inhibitors of P2X4 receptors and analysed their analgesic mechanism using an animal model of neuropathic pain.

Results

Antidepressants strongly inhibited ATP-mediated Ca2+ responses in P2X4 receptor-expressing 1321N1 cells, which are known to have no endogenous ATP receptors. Paroxetine exhibited the most powerful inhibition of calcium influx via rat and human P2X4 receptors, with IC50 values of 2.45 μM and 1.87 μM, respectively. Intrathecal administration of paroxetine produced a striking antiallodynic effect in an animal model of neuropathic pain. Co-administration of WAY100635, ketanserin or ondansetron with paroxetine induced no significant change in the antiallodynic effect of paroxetine. Furthermore, the antiallodynic effect of paroxetine was observed even in rats that had received intrathecal pretreatment with 5,7-dihydroxytryptamine, which dramatically depletes spinal 5-hydroxytryptamine.

Conclusion

These results suggest that paroxetine acts as a potent analgesic in the spinal cord via a mechanism independent of its inhibitory effect on serotonin transporters. Powerful inhibition on P2X4 receptors may underlie the analgesic effect of paroxetine, and it is possible that some antidepressants clinically used in patients with neuropathic pain show antiallodynic effects, at least in part via their inhibitory effects on P2X4 receptors.

Từ khóa


Tài liệu tham khảo

10.1111/j.1742-7843.2005.pto_96696601.x

Lynch ME, 2001, J Psychiatry Neurosci, 26, 30

10.1212/WNL.37.4.589

10.1001/jama.1984.03340370059031

10.1111/j.1365-2125.1990.tb03836.x

10.1016/0304-3959(91)90157-S

10.1007/BF02333018

10.1212/WNL.32.6.671

10.1212/WNL.38.9.1427

10.1038/clpt.1990.33

10.1212/WNL.59.7.1015

10.1056/NEJM199205073261904

10.1111/j.1533-2500.2006.00055.x

10.1016/0304-3959(90)91157-E

10.1111/j.1476-5381.1988.tb16552.x

10.1016/0028-3908(93)90173-Z

10.1016/0014-2999(81)90172-2

10.1016/j.jpain.2006.01.444

10.1016/j.jpain.2006.10.001

10.1038/nbt1194

10.1124/mol.105.020842

10.1016/0014-2999(92)90726-K

10.1038/nature01786

10.1016/0006-8993(91)90400-P

10.1016/0014-2999(89)90472-X

10.1016/0306-4522(93)90469-V

10.1016/S0014-2999(99)00350-7

10.1523/JNEUROSCI.23-17-06728.2003

10.1016/S0169-328X(98)00328-3

10.1038/sj.bjp.0703059

Khakh BS, 2001, Pharmacol Rev, 53, 107

10.1002/glia.20339

10.1016/S0006-3223(03)00074-X

10.1016/j.bcp.2006.06.003

10.1038/sj.bjp.0702955

10.1016/j.taap.2006.11.012

10.1038/clpt.1992.183

10.1016/j.tins.2004.12.002

10.1007/BF02454144

10.1016/0306-3623(91)90441-8

10.1016/j.ejphar.2004.08.048

10.1016/j.ejphar.2007.04.022

10.1213/01.ANE.0000050560.15341.A8

10.1016/j.pain.2004.03.040

10.1016/S0014-2999(00)00796-2

10.1016/0014-2999(94)00465-X

10.1006/bbrc.1996.0380

10.1016/0304-3959(92)90041-9

10.1146/annurev.pa.20.040180.002301

10.1016/0165-0270(94)90144-9

10.1038/286155a0