Prostatic acid phosphatase reduces thermal sensitivity and chronic pain sensitization by depleting phosphatidylinositol 4,5-bisphosphate.
Prostatic acid phosphatase (PAP) is expressed in nociceptive dorsal root ganglion (DRG) neurons, functions as an ectonucleotidase, and generates adenosine extracellularly. Here, we found that PAP inhibits noxious thermal sensitivity and sensitization that is associated with chronic pain through sustained activation of the adenosine A(1) receptor (A(1)R) and phospholipase C-mediated depletion of phosphatidylinositol 4,5-bisphosphate (PIP(2)). In mice, intrathecal injection of PAP reduced PIP(2) levels in DRGs, inhibited thermosensation through TRPV1, and enduringly reduced thermal hyperalgesia and mechanical allodynia caused by inflammation, nerve injury, and pronociceptive receptor activation. This included inhibitory effects on lysophosphatidic acid, purinergic (ATP), bradykinin, and protease-activated (thrombin) receptors. Conversely, PIP(2) levels were significantly elevated in DRGs from Pap(-/-) mice, and this correlated with enhanced thermal hyperalgesia and mechanical allodynia in Pap(-/-) mice. To directly test the importance of PIP(2) in nociception, we intrathecally injected PIP(2) into mice. This transiently (2 h) elevated PIP(2) levels in lumbar DRGs and transiently (2 h) enhanced thermosensation. Additionally, thermal hyperalgesia and mechanical allodynia were enduringly enhanced when PIP(2) levels were elevated coincident with injury/pronociceptive receptor stimulation. Nociceptive sensitization was not affected if PIP(2) levels were elevated in the absence of ongoing pronociceptive receptor stimulation. Together, our data suggest that PIP(2) levels in DRGs directly influence thermosensation and the magnitude of nociceptive sensitization. Moreover, our data suggest there is an underlying "phosphoinositide tone" that can be manipulated by an adenosine-generating ectonucleotidase. This tone regulates how effectively acute nociceptive insults promote the transition to chronic pain.
Sowa
Nathaniel A
NA
Department of Cell and Molecular Physiology, University of North Carolina Neuroscience Center, Chapel Hill, North Carolina 27599, USA.
Street
Sarah E
SE
Vihko
Pirkko
P
Zylka
Mark J
MJ
D000135:Acid Phosphatase; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects* / Q000502:physiology; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000494:pharmacology*; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
D019269:Phosphatidylinositol 4,5-Diphosphate; D043682:Receptor, Adenosine A1; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D000135:Acid Phosphatase; C428439:prostatic acid phosphatase; D017027:Protein Tyrosine Phosphatases; D010738:Type C Phospholipases; D002118:Calcium