Elsevier

Neuroscience

Volume 111, Issue 2, 10 May 2002, Pages 389-397
Neuroscience

Different peripheral mechanisms mediate enhanced nociception in metabolic/toxic and traumatic painful peripheral neuropathies in the rat

https://doi.org/10.1016/S0306-4522(02)00009-XGet rights and content

Abstract

Mechanisms underlying neuropathic pain states are poorly understood. We have compared mechanisms mediating enhanced nociception of four established models of neuropathic pain produced by very different types of insults to the peripheral nervous system: streptozotocin-induced hyperalgesia, a model of diabetic (metabolic) peripheral neuropathy, vincristine-induced hyperalgesia, a model of chemotherapeutic agent (toxic) peripheral neuropathy, and chronic constriction injury and partial nerve ligation, models of trauma-induced painful neuropathies.

All four models resulted in prolonged mechanical hyperalgesia (>30% decrease in mechanical nociceptive threshold) and allodynia (detected by 10–209-mN-intensity von Frey hairs). In vincristine- and streptozotocin-induced hyperalgesia, the protein kinase A, protein kinase C and nitric oxide second messenger pathways in the periphery contributed to the hyperalgesia, while N-methyl-D-aspartate (NMDA) receptor-mediated events were not detected. None of these second messengers nor the NMDA receptor, which can contribute to peripheral sensitization of nociceptors, contributed to chronic constriction injury- and partial nerve ligation-induced hyperalgesia. In all four models the hyperalgesia was not antagonized by peripheral administration of a μ-opioid agonist.

Our findings support the presence of a common abnormality in second messenger signaling in the periphery to the maintenance of two very different models of non-traumatic neuropathic pain, not shared by models of trauma-induced neuropathic pain.

Section snippets

Animals

Experiments were performed on 220–260-g male Sprague–Dawley rats (Bantin and Kingman, Fremont CA, USA). Rats were housed in groups of two under a 12-h light–dark cycle. Food and water were available ad libitum. Experiments were carried out in accordance with NIH regulations for animal care and with the approval of the Institutional Animal Care and Use Committee of the University of California, San Francisco.

Vincristine-induced (chemotherapy) painful neuropathy

Vincristine sulfate (Sigma, St. Louis, MO, USA) was dissolved in saline to a stock

Vincristine-induced hyperalgesia and allodynia

Vincristine treatment (n=16) resulted in a significant decrease in nociceptive threshold 72–168 h after the last vincristine administration, compared to normal saline treatment (n=6) (Fig. 1A; P<0.01). Evaluation of response to von Frey hair testing (10 mN through 209 mN) demonstrated a significant increase in percent frequency of paw withdrawals (Fig. 1B; both n=12; P<0.01, test done 96 h after the last vincristine administration).

Streptozotocin-induced (diabetic) hyperalgesia and allodynia

STZ treatment resulted in a significant decrease in nociceptive

Discussion

We report on a comparison of peripheral mechanisms underlying four important experimental models, of neuropathic pain states established in the rat. Although all four models manifested a similar degree of persistent mechanical hyperalgesia and allodynia, there was a significant difference in the underlying second messengers in the peripheral terminals of primary afferent nociceptors contributing to mechanical hyperalgesia. In the models of diabetic and vincristine-induced painful neuropathy the

Acknowledgements

Funded by NIH grants NS21445, NS42546 and DE08973.

References (49)

  • E Ho et al.

    Alpha-phenyl-tert-butylnitrone (PBN) inhibits NFkappaB activation offering protection against chemically induced diabetes

    Free Radic. Biol. Med.

    (2000)
  • D.L Jackson et al.

    Glutamate participates in the peripheral modulation of thermal hyperalgesia in rats

    Eur. J. Pharmacol.

    (1995)
  • S.G Khasar

    A novel nociceptor signaling pathway revealed in protein kinase C mutant mice

    Neuron

    (1999)
  • E Kinnman et al.

    Involvement of the sympathetic postganglionic neuron in capsaicin-induced secondary hyperalgesia in the rat

    Neuroscience

    (1995)
  • N.J Leidenheimer et al.

    A transient osmotic permeabilization method for the introduction of impermeant molecules into functional brain membrane vesicles

    J. Neurosci. Methods

    (1991)
  • M Nakamura-Craig et al.

    Effect of lamotrigine in the acute and chronic hyperalgesia induced by PGE2 and in the chronic hyperalgesia in rats with streptozotocin-induced diabetes

    Pain

    (1995)
  • Z Seltzer et al.

    A novel behavioral model of neuropathic pain disorders produced by partial sciatic nerve injury in rats

    Pain

    (1990)
  • C.J Woolf et al.

    Neuropathic pain: aetiology, symptoms, mechanisms, and management

    Lancet

    (1999)
  • Z.G Abbas et al.

    Evaluation of the efficacy of thiamine and pyridoxine in the treatment of symptomatic diabetic peripheral neuropathy

    East Afr. Med. J.

    (1997)
  • S Ahlgren et al.

    Protein kinase C inhibitors decrease hyperalgesia and C-fiber hyperexcitability in the streptozotocin-diabetic rat

    J. Neurophysiol.

    (1994)
  • K.O Aley et al.

    Opioid and adenosine peripheral antinociception are subject to tolerance and withdrawal

    J. Neurosci.

    (1995)
  • K.O Aley et al.

    Multiple second messenger systems act sequentially to mediate rolipram-induced prolongation of prostaglandin E2-induced mechanical hyperalgesia in the rat

    Neuroscience

    (1995)
  • K.O Aley et al.

    Dissociation of tolerance and dependence for opioid peripheral antinociception in rats

    J. Neurosci.

    (1997)
  • K.O Aley et al.

    Role of protein kinase A in the maintenance of inflammatory pain

    J. Neurosci.

    (1999)
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