Abstract
ATP induces pain via activation of purinergic receptors in nociceptive sensory nerves. ATP signaling is terminated by ATP hydrolysis mediated by cell surface-localized ecto-nucleotidases. Using enzymatic histochemical staining, we show that ecto-ATPase activity is present in mouse trigeminal nerves. Using immunofluorescence staining, we found that ecto-NTPDase3 is expressed in trigeminal nociceptive neurons and their projections to the brainstem. In addition, ecto-ATPase activity and ecto-NTPDase3 are also detected in the nociceptive outermost layer of the trigeminal subnucleus caudalis. Furthermore, we demonstrate that incubation with anti-NTPDase3 serum reduces extracellular ATP degradation in the nociceptive lamina of both the trigeminal subnucleus caudalis and the spinal cord dorsal horn. These results are consistent with neuronal NTPDase3 activity modulating pain signal transduction and transmission by affecting extracellular ATP hydrolysis within the trigeminal nociceptive pathway. Thus, disruption of trigeminal neuronal NTPDase3 expression and localization to presynaptic terminals during chronic inflammation, local constriction and injury may contribute to the pathogenesis of orofacial neuropathic pain.
Highlights
Noxious stimuli or pain mediators released following tissue injury or inflammation activate nociceptors in peripheral sensory nerve fibers
We detected positive staining for functional ecto-ATPase activity in trigeminal nerve fibers projecting to the brainstem (Fig 1C)
Our ecto-ATPase activity blocking experiment showed that incubation with anti-NTPDase3 serum only partially reduced the ecto-ATPase activity in the nociceptive lamina. While these results indicate that NTPDase3 mediates extracellular ATP degradation in trigeminal nociceptive lamina, they leave open the possible role of alternative ecto-ATPases and illustrate the complexity of ATP hydrolysis mechanisms in the nociceptive lamina
Summary
Noxious stimuli or pain mediators released following tissue injury or inflammation activate nociceptors in peripheral sensory nerve fibers. Noxious stimulation of trigeminal nerves that innervate orofacial tissue results in transduction of the pain signal to secondary nociceptive neurons in the brainstem trigeminal subnucleus caudalis. Pain sensation depends on the condition and status of the sensory nervous system. As sensitization occurs within the nociceptive signal pathway, severe pain is induced by slight noxious stimulation or even non-noxious stimulation. ATP and its metabolites are important pain mediators and modulators of pain signal processing in nociceptive sensory nerves [2,3,4,5]. Purinergic P2X receptors are expressed in trigeminal nerve fibers [6] and ATP induces pain by activation
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