Downregulation of adenosine and adenosine A1 receptor contributes to neuropathic pain in resiniferatoxin neuropathy.

Abstract

The neurochemical effects of adenosine signaling in small-fiber neuropathy leading to neuropathic pain are yet to be explored in a direct manner. This study examined this system at the level of ligand (through the ectonucleotidase activity of prostatic acid phosphatase [PAP]) and adenosine A1 receptors (A1Rs) in resiniferatoxin (RTX) neuropathy, a peripheral neurodegenerative disorder that specifically affects nociceptive nerves expressing transient receptor potential vanilloid type 1 (TRPV1). We conducted immunohistochemistry on dorsal root ganglion (DRG) neurons, high-performance liquid chromatography for functional assays, and pharmacological interventions to alter PAP and A1Rs in mice with RTX neuropathy. In DRG of RTX neuropathy, PAP(+) neurons were reduced compared with vehicle-treated mice (P = 0.002). Functionally, PAP ectonucleotidase activity was consequently reduced (ie, the content of adenosine in DRG, P = 0.012). PAP(+) neuronal density was correlated with the degree of mechanical allodynia, which was reversed by intrathecal (i.t.) lumbar puncture injection of recombinant PAP with a dose-dependent effect. Furthermore, A1Rs were downregulated (P = 0.002), and this downregulation was colocalized with the TRPV1 receptor (31.0% ± 2.8%). Mechanical allodynia was attenuated in a dose-dependent response by i.t. injection of the A1R ligand, adenosine; however, no analgesia was evident when an exogenous adenosine was blocked by A1R antagonist. This study demonstrated dual mechanisms of neuropathic pain in TRPV1-induced neuropathy, involving a reduced adenosine system at both the ligand (adenosine) and receptor (A1Rs) levels.

• Authors: Hung-Wei Kan, Chin-Hong Chang, Chih-Lung Lin, Yi-Chen Lee, Sung-Tsang Hsieh, Yu-Lin Hsieh
• Journal: Pain (Pain) Vol. 159 Issue 8 Pg. 1580-1591 (Aug 2018) ISSN: 1872-6623 [Electronic] United States
• PMID: 29672450 (Publication Type: Journal Article)

Chemical References

• Diterpenes
• Neurotoxins
• Receptor, Adenosine A1
• resiniferatoxin
• Adenosine

Topics

• Adenosine (metabolism)
• Animals
• Diterpenes (toxicity)
• Down-Regulation (drug effects)
• Ganglia, Spinal (drug effects, metabolism)
• Mice
• Neuralgia (etiology, metabolism)
• Neurons (drug effects, metabolism)
• Neurotoxins (toxicity)
• Pain Measurement
• Receptor, Adenosine A1 (metabolism)
• Small Fiber Neuropathy (chemically induced, complications, metabolism)