CNGA3: A Target of Spinal Nitric Oxide/cGMP Signaling and Modulator of Inflammatory Pain Hypersensitivity

Abstract

A large body of evidence indicates that nitric oxide (NO) and cGMP contribute to central sensitization of pain pathways during inflammatory pain. Here, we investigated the distribution of cyclic nucleotide-gated (CNG) channels in the spinal cord, and identified the CNG channel subunit CNGA3 as a putative cGMP target in nociceptive processing. In situ hybridization revealed that CNGA3 is localized to inhibitory neurons of the dorsal horn of the spinal cord, whereas its distribution in dorsal root ganglia is restricted to non-neuronal cells. CNGA3 expression is upregulated in the superficial dorsal horn of the mouse spinal cord and in dorsal root ganglia following hindpaw inflammation evoked by zymosan. Mice lacking CNGA3 (CNGA3 Ϫ/Ϫ mice) exhibited an increased nociceptive behavior in models of inflammatory pain, whereas their behavior in models of acute or neuropathic pain was normal. Moreover, CNGA3 Ϫ/Ϫ mice developed an exaggerated pain hypersensitivity induced by intrathecal administration of cGMP analogs or NO donors. Our results provide evidence that CNGA3 contributes in an inhibitory manner to the central sensitization of pain pathways during inflammatory pain as a target of NO/cGMP signaling.

Antioxidant Activity of Sestrin 2 Controls Neuropathic Pain After Peripheral Nerve Injury

“…Probe generation and in situ hybridization was performed as previously described (8). Briefly, cDNA synthesis was performed with gene specific primers 5¢-gga gtg tct atc gcc gta ga-3¢ and 5¢-taa gaa cac tgg tga cgg gc-3¢ corresponding to the nucleotides 140-664 of Sesn2 mRNA (NCBI accession number NM_144907.1).…”

“…Immunofluorescence staining of spinal cord and DRG slides was performed as previously described (8,17). Briefly, animals were intracardially perfused with 4% PFA, and dissected lumbar spinal cord (L4-L5) and DRGs (L4-L5) were cryostat sectioned at a thickness of 14-16 lm and stored at -80°C until use.…”

“…This device pushes a thin steel rod against the plantar surface of the paw from beneath, and automatically stops and records the latency time at which the animal withdraws the paw. The force was increased constantly from 0 to 5 g in 10 s (ramp 0.5 g/s) and remained at 5 g for an additional 10 s (8,28). Paw withdrawal latency was calculated as the mean of 4-6 measurements with at least 20 s in between.…”

NADPH Oxidase-4 Maintains Neuropathic Pain after Peripheral Nerve Injury

“…This device pushes a thin probe (0.5 mm diameter) with increasing force through a wire-grated floor against the plantar surface of the paw from beneath, and it automatically stops and records the latency time at which the animal withdraws the paw. The force increased from 0 to 5 g in 10 s (0.5 g/s ramp) and was then held at 5 g for an additional 10 s (Schmidtko et al, 2008b;Heine et al, 2011). The latency time was calculated as the average of four to six consecutive exposures with at least 20 s in between.…”

Analgesic effects and possible mechanisms of iridoid glycosides from Lamiophlomis rotata (Benth.) Kudo in rats with spared nerve injury

“…Cyclic guanosine monophosphate (cGMP) is also known to be a major mediator of NO, and intracellular elevation of cGMP levels may further activate cGMP dependent protein kinase G (PKG) (Ji and Woolf, 2001;Wang and Robinson, 1997). Previous studies further confirm that activation of the NO/cGMP/PKG signaling pathway influences the pathogenesis of neuropathic pain (Heine et al, 2011). Therefore, the aim of the present study was to explore whether IGLR produce an anti-neuropathic pain effect and whether the cytokines from glia cells, the NMDAR/PKC and NO/cGMP/ PKG neuronal pathways are involved in mediating this effect.…”