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1 Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, California.
2 Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, California; Department of Medicine, University of California San Francisco, San Francisco, California. Electronic address: [email protected].
1 Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, California.
2 Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, California; Department of Medicine, University of California San Francisco, San Francisco, California. Electronic address: [email protected].
We hypothesized that changes in the expression of voltage-gated potassium channel (Kv) 4.3 contribute to the mechanical hyperalgesia induced by vibration injury, in a rodent model for hand-arm vibration syndrome in humans. Here we show that the exposure of the gastrocnemius muscle to vibration injury induces muscle hyperalgesia that is accompanied by a significant downregulation of Kv4.3 in affected sensory nerve fibers in dorsal root ganglia. We additionally show that the intrathecal administration of antisense oligonucleotides for Kv4.3 messenger RNA itself induces muscle hyperalgesia in the rat. Our results suggest that attenuation in the expression of Kv4.3 may contribute to neuropathic pain in people affected by hand-arm vibration syndrome.
Perspective:
Our findings establish Kv4.3 as a potential molecular target for the treatment of hand-arm vibration syndrome.
Figure 1. Muscle vibration induces mechanical hyperalgesia in skeletal muscle
A significant decrease of 24.4…
Figure 1. Muscle vibration induces mechanical hyperalgesia in skeletal muscle
A significant decrease of 24.4 ± 1.3% (n=9 per group) in nociceptive threshold in the gastrocnemius muscle, hyperalgesia, was observed 24 hours after vibration injury. Nociceptive threshold was defined as the force in milliNewtons (mN) at which the rat withdrew its hind leg from the force transducer applied to the belly of the muscle. *** P
Figure 2. Vibration induced changes in Kv…
Figure 2. Vibration induced changes in Kv 4.3 mRNA in DRG
Analysis of Kv 4.3…
Figure 2. Vibration induced changes in Kv 4.3 mRNA in DRG
Analysis of Kv 4.3 mRNA expression in L4 and L5 DRG 24 hours after vibration injury to the hind limb gastrocnemius muscles: (A) A semi-quantitative RT-PCR analysis was performed comparing injured and uninjured animals. The density of the PCR product of the Kv 4.3 gene at 301 bp was normalized to the density of the PCR product of the S18 rRNA standard at 324 bp. (B) A significant down-regulation of Kv 4.3 mRNA (8.03 ± 2.3%, n=3 per group) was observed after vibration injury, in comparison to the non-vibrated control. * P < 0.01.
Figure 3. Vibration induced changes in NRSF…
Figure 3. Vibration induced changes in NRSF protein expression
Western blot analysis of NRSF protein…
Figure 3. Vibration induced changes in NRSF protein expression
Western blot analysis of NRSF protein levels in L4 and L5 bilateral DRG neurons. (A) β-actin, used as a housekeeping gene in this analysis, has the calculated molecular weight of ~42 kDa; the calculated molecular weight of NRSF is ~117 kDa. (B) A detectable but non-significant increase in NRSF 10.0 ± 8.2 % (n=9 per group) was present after vibration injury. Values are represented as mean percent of NRSF expression in comparison to β-actin band intensity.
Figure 4. Effect of intrathecal AS/MM ODN…
Figure 4. Effect of intrathecal AS/MM ODN directed against Kv4.3 mRNA on muscle mechanical nociceptive…
Figure 4. Effect of intrathecal AS/MM ODN directed against Kv4.3 mRNA on muscle mechanical nociceptive threshold
Attenuation of Kv 4.3 mRNA with three consecutive intrathecal injections of AS-ODN (open symbols, n=6) resulted in a 42.2 ± 1.1% reduction in nociceptive threshold, with no significant changes in the MM-ODN group (black symbols, n=6). This finding supports the suggestion that the down-regulation of Kv 4.3 contributes to the mechanical hyperalgesia observed in our rodent model for hand-arm vibration syndrome. Black arrows indicate time points of ODN injections. ***P
Ahlgren SC, White DM, Levine JD. Increased responsiveness of sensory neurons in the saphenous nerve of the streptozotocin-diabetic rat. J Neurophysiol. 1992;68:2077–2085.
-
PubMed
Aley KO, Messing RO, Mochly-Rosen D, Levine JD. Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C. J Neurosci. 2000;20:4680–4685.
-
PMC
-
PubMed
Alvarez P, Chen X, Bogen O, Green PG, Levine JD. IB4(+) nociceptors mediate persistent muscle pain induced by GDNF. J Neurophysiol. 2012;108:2545–2553.
-
PMC
-
PubMed
Alvarez P, Gear RW, Green PG, Levine JD. IB4-saporin attenuates acute and eliminates chronic muscle pain in the rat. Exp Neurol. 2012;233:859–865.
-
PMC
-
PubMed
Alvarez P, Green PG, Levine JD. Role for monocyte chemoattractant protein-1 in the induction of chronic muscle pain in the rat. Pain. 2014;155:1161–1167.
-
PMC
-
PubMed
