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The Journal of Neuroscience, August 18, 2004, 24(33):7283-7291; doi:10.1523/JNEUROSCI.0983-04.2004

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Development/Plasticity/Repair
Pituitary Adenylate Cyclase-Activating Polypeptide Is Required for the Development of Spinal Sensitization and Induction of Neuropathic Pain

Tamaki Mabuchi,^1 * Norihito Shintani,^2 * Shinji Matsumura,¹ Emiko Okuda-Ashitaka,¹ Hitoshi Hashimoto,² Tadatoshi Muratani,⁴ Toshiaki Minami,⁴ Akemichi Baba,^2,3 and Seiji Ito¹

¹Department of Medical Chemistry, Kansai Medical University, Moriguchi 570-8506, Japan, ²Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, and ³Laboratory of Molecular Pharmacology, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan, and ⁴Department of Anesthesiology, Osaka Medical College, Takatsuki 569-8686, Japan

The prolonged sensitization of pain transmission after nerve injury by increasing excitability of spinal neurons and thereby promoting repair is an adaptive response of the body. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is widely distributed in the nervous system and implicated in neurotransmission, neural plasticity, and neurotrophic actions. Although PACAP is distributed in the spinal cord and dorsal root ganglia, a role of PACAP in pain responses remains essentially unknown. Here we show that mice lacking the PACAP gene (PACAP^-/-) did not exhibit inflammatory pain induced by intraplantar injection of carrageenan or neuropathic pain induced by L5 spinal nerve transection, whereas they did retain normal nociceptive responses. Intrathecal administration of NMDA induced mechanical allodynia in wild-type mice, but not in PACAP^-/- mice. The NMDA-induced allodynia in PACAP^-/- mice was reproduced by simultaneous intrathecal injection of PACAP with NMDA. Concomitant with the increase in PACAP immunoreactivity after nerve injury, NADPH-dependent nitric oxide synthase (NOS) activity visualized by NADPH diaphorase histochemistry markedly increased in the superficial layer of the spinal cord of wild-type mice, which was not observed in PACAP^-/- mice. Simultaneous addition of PACAP and NMDA caused translocation of neuronal NOS from the cytosol to the membrane and stimulated NO production in vitro. These results demonstrate that PACAP might promote the functional coupling of neuronal NOS to NMDA receptors for both inflammatory and neuropathic pain to occur.

Key words: PACAP; knock-out mice; pain; NMDA; nitric oxide synthase; translocation

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Received March 17, 2004; revised July 12, 2004; accepted July 13, 2004.

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