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. 2008 Sep;28(6):1180-90.
doi: 10.1111/j.1460-9568.2008.06425.x. Epub 2008 Sep 9.

Neurotoxic catecholamine metabolite in nociceptors contributes to painful peripheral neuropathy

Olayinka A Dina  1 , Sachia G Khasar, Nicole Alessandri-Haber, Oliver Bogen, Xiaojie Chen, Paul G Green, David B Reichling, Robert O Messing, Jon D Levine
Affiliations

Neurotoxic catecholamine metabolite in nociceptors contributes to painful peripheral neuropathy

Olayinka A Dina et al. Eur J Neurosci. 2008 Sep.

Erratum in

Abstract

The neurotoxic effects of catecholamine metabolites have been implicated in neurodegenerative diseases. As some sensory neurons express tyrosine hydroxylase and monoamine oxidase (MAO), we investigated the potential contribution of catecholamine metabolites to neuropathic pain in a model of alcoholic neuropathy. The presence of catecholamines in sensory neurons is supported by capsaicin-stimulated epinephrine release, an effect enhanced in ethanol-fed rats. mRNA for enzymes in dorsal root ganglia involved in catecholamine uptake and metabolism, dopamine beta-hydroxylase and MAO-A, were decreased by neonatal administration of capsaicin. Ethanol-induced hyperalgesia was attenuated by systemic and local peripheral administration of inhibitors of MAO-A, reduction of norepinephrine transporter (NET) in sensory neurons and a NET inhibitor. Finally, intradermal injection of 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), a neurotoxic MAO-A catecholamine metabolite, produced robust mechanical hyperalgesia. These observations suggest that catecholamines in nociceptors are metabolized to neurotoxic products by MAO-A, which can cause neuronal dysfunction underlying neuropathic pain.

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Figures

Figure 1
Figure 1
A) Synthetic and B) metabolic pathways of catecholamines (Flatmark, 2000; Eisenhofer et al., 2004) Abbreviations: ADH - alcohol dehydrogenase, AR - aldehyde reductase, COMT - catechol-O-methyltransferase, DβH - Dopamine β-hydroxylase, DHPG - 3,4-dihydorxyphenylglycol, DOPEGAL - 3,4-dihydroxyphenylglycolaldehyde, L-DOPA - dihyrdoxyphenylalanine, MAO - monoamine oxidase, MHPG - 3-methoxy-4-hydroxyphenylglycol, PNMT - phenylethanolamine N-methyltransferase, TH - tyrosine hydroxylase, VMA - vanillylmadelic acid.
Figure 2
Figure 2
Effect of lumbar surgical sympathectomy on tyrosine hydroxylase-positive profiles in lumbar dorsal root ganglia (DRG). Compared with DRG from control rats (left panel), in which tyrosine hydroxylase immunoreactive profiles were plentiful, such profiles were only rarely observed in DRG from rats that had undergone surgical lumbar sympathectomy 14 days prior, and had the appearance of degenerating axons (right panel). Scale bar = 50 μm. B) Semiquantitative RT-PCR for NET, DβH and MAO-A in rats that were neonatally treated with capsaicin or vehicle (control). For DβH, there was a 47 ± 3% decrease (p < 0.001) and for MAO-A, there was a 54 ± 5% decrease (p = 0.002) in mRNA expression in capsaicin-treated rats. There was no significant change in NET mRNA expression in capsaicin-treated rats (p > 0.05). In each case, n = 2 for control and n = 4 for capsaicin-treated rats (unpaired two-tailed Student's t test).
Figure 3
Figure 3
Effect of administration of monoamine oxidase (MAO) inhibitors, on ethanol-induced hyperalgesia. A) There was no decrease in nociceptive threshold, for up to 3 weeks, when rats were fed ethanol diet (ED) during administration of MAO-A inhibitor, clorgyline (2 mg/kg/day subcutaneously (s.c.)) (F(2, 36) = 160.0, p < 0.001), until after it was stopped. The MAO-B inhibitor, pargyline (25 mg/kg/day, s.c.), did not prevent the development of ethanol-induced hyperalgesia (p > 0.05) compared with alcohol alone. B) Twelve rats were fed ED for 3 weeks, then clorgyline (2 mg/kg/day, s.c.) was administered to 4 of the rats and pargyline (25 mg/kg/day s.c.) to another 4, while the remaining 4 received vehicle. All rats continued to be fed ED for the duration of the experiment. One week after the commencement of MAO inhibitor administration, there were significant differences between the groups (F(2, 91) = 28.1, p < 0.001). Nociceptive thresholds of MAO-A but not MAO-B inhibitor-treated rats returned to about 85% of the pre-ethanol baseline after 1 week and to pre-ethanol baseline after 2 weeks (p < 0.001) from weeks 5 to 6. When MAO-A administration was stopped, ethanol-induced hyperalgesia re-appeared. C) A single intradermal administration of clorgyline (100 ng/2.5 μl) attenuated ethanol-induced hyperalgesia for a period of about 3 hours.
Figure 4
Figure 4
Dose-response and time-dependence for the effect of DOPEGAL (0.1 ng-1.0 μg) on mechanical nociceptive threshold when injected intradermally into hind paws of alcohol-naïve rats. Nociceptive thresholds were measured over a period of 48 hours starting 30 minutes after injection of DOPEGAL (F(4, 60) = 66.4, p 0.05, n = 4 for each dose).
Figure 5
Figure 5
A) NET inhibitor, desipramine (DMI), attenuated ethanol diet-induced hyperalgesia (F(1,70) = 30.1, p < 0.001). Significant inhibition of alcohol-induced hyperalgesia occurred from days 33-37. Desipramine (20 mg/kg/day, s.c.) was administered, for 14 days to rats that had already been fed the ethanol diet for 3 weeks and had developed mechanical hyperalgesia. B) Reversal of ethanol-induced hyperalgesia by a single intradermal injection of desipramine (100 ng) into the hind paws of rats after 3 weeks of ethanol consumption (F(1, 42) = 507.6, p < 0.001). Alcohol-induced hyperalgesia was significantly inhibited by intradermal desipramine from 30 minutes to 4 hours. This effect of desipramine was no longer detectable after 24 hours.
Figure 6
Figure 6
A) Attenuation of ethanol-induced hyperalgesia by NET antisense. After 3 weeks of being fed ethanol diet and while still on this diet, rats were treated intrathecally with ODN antisense or mismatch to NET (40 μg/20 μl), for 5 days. Antisense produced attenuation of alcohol-induced hyperalgesia compared to mismatch, (F(1,130) = 64.30, p < 0.001). Alcohol-induced hyperalgesia was significantly reversed from days 25-28). Three days after the last dose of antisense, hyperalgesia was re-established. B) NET antisense produced a 34 ± 3% reduction in a specific 80 kDa band detected by Western blot analysis in ligated saphenous nerves compared with mismatch-treated rats (n = 5 for each group, p = 0.01, unpaired Student's t-test).
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