Analgesic profile of intrathecal P2X(3) antisense oligonucleotide treatment in chronic inflammatory and neuropathic pain states in rats.
Extracellular adenosine triphosphate (ATP), acting at P2X ionotropic receptors, is implicated in numerous sensory processes. Exogenous ATP has been shown to be algogenic in both animals and humans. Research focus has been directed towards the P2X(3) receptor, as it is preferentially expressed on nociceptive C-fibers and its implication in pain processing is supported by an altered nociceptive phenotype in P2X(3) knock-out mice. In order to further characterize the role of P2X(3) receptor activation in nociception, we evaluated the effects of continuous intrathecal administration of P2X(3) antisense oligonucleotides for 7 days in the rat. P2X(3) receptor antisense oligonucleotide treatment significantly decreased nociceptive behaviors observed after injection of complete Freund's adjuvant (CFA), formalin or alphabeta-methylene ATP into the rat's hind paw. The anti-hyperalgesic effects of the antisense treatment in the CFA model of inflammatory pain were dose related. Similar effects were observed with two distinct P2X(3) antisense oligonucleotides. These behavioral effects were significantly correlated with a decrease in P2X(3) receptor protein expression in the dorsal root ganglia (DRG). In contrast, a decrease in P2X(3) receptor protein expression in the DRG did not affect nociceptive behavior in the carrageenan model of acute thermal hyperalgesia. P2X(3) receptor antisense oligonucleotide treatment also significantly reduced mechanical allodynia observed after spinal nerve ligation. Overall, the present data demonstrate that activation of P2X(3) receptors contribute to the expression of chronic inflammatory and neuropathic pain states and that relief form these forms of chronic pain might be achieved by selective blockade of P2X(3 )receptor expression or activation.
Honore
Prisca
P
Abbott Laboratories, Neuroscience Research, Global Pharmaceutical Research and Development, 100 Abbott Park Road, Abbott Park, IL 60064, USA. marie.honore@ln.ssw.abbott.com
Kage
Karen
K
Mikusa
Joseph
J
Watt
Andrew T
AT
Johnston
Joseph F
JF
Wyatt
Jacqueline R
JR
Faltynek
Connie R
CR
Jarvis
Michael F
MF
Lynch
Kevin
K
D000208:Acute Disease; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002908:Chronic Disease; D006930:Hyperalgesia / Q000628:therapy; D007278:Injections, Spinal; D008026:Ligation; D008297:Male; D009437:Neuralgia / Q000628:therapy*; D020078:Neurogenic Inflammation / Q000628:therapy*; D009619:Nociceptors / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000235:genetics*; D058477:Receptors, Purinergic P2X3; D013127:Spinal Nerves / Q000502:physiology
D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; C546407:P2RX3 protein, human; C546409:P2rx3 protein, mouse; C546410:P2rx3 protein, rat; D018048:Receptors, Purinergic P2; D058477:Receptors, Purinergic P2X3; D000255:Adenosine Triphosphate; C002630:alpha,beta-methyleneadenosine 5'-triphosphate