Evidence for the involvement of spinal endogenous ATP and P2X receptors in nociceptive responses caused by formalin and capsaicin in mice.

1. The aim of the present study is to characterize the role of spinal endogenous ATP and P2X receptors in the generation of neurogenic and inflammatory pain. We examined the effects of intrathecal treatment with P2X receptor antagonists on the formalin- and capsaicin-induced nociceptive behaviours in mice. 2. Intrathecal pretreatment with the general P2 receptor antagonist, pyridoxal-phosphate-6-azophenyl-2', 4'-disulphonic acid (PPADS), significantly suppressed both the first and second phases of the formalin-induced nociceptive behaviour. The second phase of the nociceptive response was also suppressed by intrathecal treatment with PPADS after the first phase. Furthermore, pretreatment with the selective antagonist for the P2X1, P2X3 and P2X2+3 receptors, 2',3'-O-(2,4,6-trinitrophenyl)adenosine 5'-triphosphate (TNP-ATP), significantly reduced the first phase, but not the second phase. The second phase was also not suppressed by intrathecal TNP-ATP after the first phase. 3. Capsaicin-induced nociceptive behaviour that has been shown to be a model for neurogenic pain, was also significantly suppressed by intrathecal pretreatment with PPADS or TNP-ATP. 4. Nociceptive behaviour in the first phase of the formalin test and in the capsaicin test were significantly inhibited by intrathecal pretreatment with alpha, beta-methylene ATP (alpha,betameATP: 5 microg mouse-1) 15 min prior to injection of formalin or capsaicin. This treatment has been previously shown to desensitize spinal P2X3 receptor subtypes in vivo. 5. These findings suggest that spinal endogenous ATP may play a role in (1) the formalin- and capsaicin-induced neurogenic pain via the PPADS- and TNP-ATP-sensitive P2X receptors which are also desensitized by alpha,betameATP (perhaps the P2X3 receptor subtype) and (2) formalin-induced inflammatory pain via PPADS-sensitive, TNP-ATP- and alpha,betameATP-insensitive P2X (and/or P2Y) receptors.