The emergence of adolescent onset pain hypersensitivity following neonatal nerve injury

Vega-Avelaira David, Mckelvey Rebecca, Hathway Gareth, Fitzgerald, Fitzgerald Maria

Description

Peripheral nerve injuries can trigger neuropathic pain in adults but cause little or no pain when they are sustained in infancy or early childhood. This is confirmed in rodent models where neonatal nerve injury causes no pain behaviour. However, delayed pain can arise in man some considerable time after nerve damage and to examine this following early life nerve injury we have carried out a longer term follow up of rat pain behaviour into adolescence and adulthood. Results Spared nerve injury (SNI) or sham surgery was performed on 10 day old (P10) rat pups and mechanical nociceptive reflex thresholds were analysed 3, 7, 14, 21, 28, 38 and 44 days post surgery. While mechanical thresholds on the ipsilateral side are not significantly different from controls for the first 2–3 weeks post P10 surgery, after that time period, beginning at 21 days post surgery (P31), the SNI group developed following early life nerve injury significant hypersensitivity compared to the other groups. Ipsilateral mechanical nociceptive threshold was 2-fold below that of the contralateral and sham thresholds at 21 days post surgery (SNI-ipsilateral 28 (±5) g control groups 69 (±9) g, p < 0.001, 3-way ANOVA, n = 6 per group). Importantly, no effect was observed on thermal thresholds. This hypersensivity was accompanied by macrophage, microglial and astrocyte activation in the DRG and dorsal horn, but no significant change in dorsal horn p38 or JNK expression. Preemptive minocycline (daily 40 mg/kg, s.c) did not prevent the effect. Ketamine (20 mg/kg, s.c), on the other hand, produced a dose-dependent reversal of mechanical nociceptive thresholds ipsilateral to the nerve injury such that thresholds return to control levels at the highest doses of 20 mg/Kg. Conclusions We report a novel consequence of early life nerve injury whereby mechanical hypersensitivity only emerges later in life. This delayed adolescent onset in mechanical pain thresholds is accompanied by neuroimmune activation and NMDA dependent central sensitization of spinal nociceptive circuits. This delayed onset in mechanical pain sensitivity may provide clues to understand the long term effects of early injury such as late onset phantom pain and the emergence of complex adolescent chronic pain syndromes.

Sujets

• Neuropathic pain
• Microglía
• Spinal cord
• Dorsal root ganglion
• Néonatalogie

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 9
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

VegaAvelairaet al. Molecular Pain2012,8:30 http://www.molecularpain.com/content/8/1/30

MOLECULAR PAIN

R E S E A R C HOpen Access The emergence of adolescent onset pain hypersensitivity following neonatal nerve injury 1,3* 12 1 David VegaAvelaira, Rebecca McKelvey , Gareth Hathwayand Maria Fitzgerald

Abstract Background:Peripheral nerve injuries can trigger neuropathic pain in adults but cause little or no pain when they are sustained in infancy or early childhood. This is confirmed in rodent models where neonatal nerve injury causes no pain behaviour. However, delayed pain can arise in man some considerable time after nerve damage and to examine this following early life nerve injury we have carried out a longer term follow up of rat pain behaviour into adolescence and adulthood. Results:Spared nerve injury (SNI) or sham surgery was performed on 10 day old (P10) rat pups and mechanical nociceptive reflex thresholds were analysed 3, 7, 14, 21, 28, 38 and 44 days post surgery. While mechanical thresholds on the ipsilateral side are not significantly different from controls for the first 2–3 weeks post P10 surgery, after that time period, beginning at 21 days post surgery (P31), the SNI group developed following early life nerve injury significant hypersensitivity compared to the other groups. Ipsilateral mechanical nociceptive threshold was 2fold below that of the contralateral and sham thresholds at 21 days post surgery (SNIipsilateral 28 (±5) g control groups 69 (±9) g, p<0.001, 3way ANOVA, n= 6 per group). Importantly,no effect was observed on thermal thresholds. This hypersensivity was accompanied by macrophage, microglial and astrocyte activation in the DRG and dorsal horn, but no significant change in dorsal horn p38 or JNK expression. Preemptive minocycline (daily 40 mg/kg, s.c) did not prevent the effect. Ketamine (20 mg/kg, s.c), on the other hand, produced a dosedependent reversal of mechanical nociceptive thresholds ipsilateral to the nerve injury such that thresholds return to control levels at the highest doses of 20 mg/Kg. Conclusions:We report a novel consequence of early life nerve injury whereby mechanical hypersensitivity only emerges later in life. This delayed adolescent onset in mechanical pain thresholds is accompanied by neuroimmune activation and NMDA dependent central sensitization of spinal nociceptive circuits. This delayed onset in mechanical pain sensitivity may provide clues to understand the long term effects of early injury such as late onset phantom pain and the emergence of complex adolescent chronic pain syndromes. Keywords:Neuropathic pain, Microglia, Astrocytes, Spinal cord, Dorsal root ganglia, Neonatal

Introduction It is well documented that neuropathic pain is absent or transient in the youngest infants or children. Brachial plexus injuries at birth, followed by nerve repair, are not associated with pain [1] and reports of phantom pain, complex regional pain syndrome, peripheral neuropathy pain are very rare before 5–6 years of age [2]. This is supported by animal models of neuropathic pain, spared nerve injury (SNI) and chronic constriction injury (CCI), where little or

* Correspondence: [e-mail] 1 UCL Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E6BT, UK 3 Current address: Dpto. Fisiología, Edificio Medicina, Universidad Alcalá, Madrid, 28871, Spain Full list of author information is available at the end of the article

no allodynia and pain behaviour is observed in animals whose nerves have been injured before three weeks of age or postnatal day 21 (P21) [35]. The aim of the current study was to investigate the longer term effects of early nerve injury and to test whether pain or hypersensitivity might emerge beyond the post injury period, perhaps only in adolescence. To date, the longer term effects of nerve injury, and the possibility of emergence of pain be yond childhood has not specifically been addressed [68]. Most studies of nerve injury in infants have not followed up the long term consequences; obstetric injuries in man have been followed up for only for about 7 years and experimental nerve injury rat pups, only for a few weeks [5]. Intriguing clues exist in the clinical literature that symptoms may

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