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. 2015 Jan 22:284:678-684.
doi: 10.1016/j.neuroscience.2014.10.056. Epub 2014 Nov 4.

Homocysteine-induced attenuation of vascular endothelium-dependent hyperalgesia in the rat

E K Joseph  1 , P G Green  1 , L F Ferrari  1 , J D Levine  2
Affiliations

Homocysteine-induced attenuation of vascular endothelium-dependent hyperalgesia in the rat

E K Joseph et al. Neuroscience. .

Abstract

We have recently demonstrated a role of the vascular endothelium in peripheral pain mechanism by disrupting endothelial cell function using intravascular administration of octoxynol-9, a non-selective membrane active agent. As an independent test of the role of endothelial cells in pain mechanisms, we evaluated the effect of homocysteine, an agent that damages endothelial cell function. Mechanical stimulus-induced enhancement of endothelin-1 hyperalgesia in the gastrocnemius muscle of the rat was first prevented then enhanced by intravenous administration of homocysteine, but was only inhibited by its precursor, methionine. Both homocysteine and methionine significantly attenuated mechanical hyperalgesia in two models of ergonomic muscle pain, induced by exposure to vibration, and by eccentric exercise, and cutaneous mechanical hyperalgesia in an ischemia-reperfusion injury model of Complex Regional Pain Syndrome type I, all previously shown responsive to octoxynol-9. This study provides independent support for a role of the endothelial cell in pain syndromes thought to have a vascular basis, and suggests that substances that are endothelial cell toxins can enhance vascular pain.

Keywords: homocysteine; methionine endothelium; muscle pain; vascular pain.

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Conflict of interest statement

The authors report no conflicts of interest.

Figures

Figure 1
Figure 1. Effect of methionine and homocysteine on ET-1 hyperalgesia and stimulus-dependent hyperalgesia cutaneous cutaneously
ET-1 (100 ng, i.d. on dorsum of the hind paw) induced mechanical hyperalgesia (reading 1, 15 min post-administration) that was enhanced by repeat threshold intensity stimuli applied at the site of nociceptive testing (i.e. stimulus-dependent hyperalgesia). A. Intravenous administration of methionine (1 mg/kg) or homocysteine (3 mg/kg), 30 min before ET-1, markedly attenuated the ET-1 hyperalgesia, and completely eliminated stimulus-dependent hyperalgesia. B. Intravenous administration methionine (1 mg/kg) or homocysteine (3 mg/kg), 3 h before ET-1 did not affect ET-1 hyperalgesia. Stimulus-dependent hyperalgesia was completely eliminated by methionine but not by homocysteine at the 3 h pretreatment time point. C. Intradermal administration methionine (1 μg) or homocysteine (5 μg) 30 min before ET-1 markedly attenuated ET-1 hyperalgesia, and completely eliminated stimulus-dependent hyperalgesia. D. Intradermal administration methionine (1 μg) or homocysteine (5 μg) 3 h before ET-1 did not affect ET-1 hyperalgesia. Stimulus-dependent hyperalgesia was completely eliminated by methionine but enhanced by homocysteine, at the 3 h pretreatment time point.
Figure 2
Figure 2. Effect of intravenous methionine and homocysteine on muscle hyperalgesia and stimulus-dependent hyperalgesia produced by ischemia-reperfusion injury
Exposure to either hind limb vibration (A) or eccentric exercise (B) produced a marked decrease in mechanical nociceptive threshold in the ipsilateral gastrocnemius muscle. Intravenous administration of either methionine (1 mg/kg) or homocysteine (3 mg/kg) prevented this hyperalgesia when evaluated 30 min and 3 h after administration.
Figure 3
Figure 3. Effect of intravenous methionine and homocysteine on muscle hyperalgesia and stimulus-dependent hyperalgesia produced by vibration and by eccentric exercise
Intravenous administration of: (A) methionine (1 mg/kg) or (B) homocysteine (3 mg/kg), markedly attenuated the hyperalgesia induced by ischemia reperfusion, evaluated 30 min and 3 h after administration.
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