Involvement of increased excitatory amino acids and intracellular Ca2+ concentration in the spinal dorsal horn in an animal model of neuropathic pain

Abstract

Neuropathic pain following nerve injury is believed to involve excitatory amino acids (EAAs) and Ca2+-mediated neuronal plastic changes in the central nervous system (CNS). This study was designed to investigate the changes in glutamate and aspartate contents in the dorsal half of the spinal cord following chronic constrictive injury (CCI) of the rat common sciatic nerve. We also examined the changes in intracellular calcium ion concentration ([Ca2+]i) of the spinal dorsal horn in transverse spinal slices in the same animal model. Thermal and mechanical hyperalgesia were observed on day 2 and thereafter following CCI (P < 0.0001). In the CCI rats to which 0.5 mg/kg of i.p. MK-801 was given 30 min prior to CCI and subsequently three daily treatments with 0.5 mg/kg of i.p. MK-801, the development of thermal and mechanical hyperalgesia was suppressed for a period of up to 7 days; however, hyperalgesia appeared on day 10 and day 14 (P < 0.001). In CCI rats, significant increases were observed in glutamate and aspartate contents on the ipsilateral side of the dorsal horn to nerve ligation on days 4, 7 and 14 (P < 0.001). Moreover, significant increases in [Ca2+]i in the spinal dorsal horn were also observed in the superficial (lamina I-II) and deep layers (lamina V-VI) on the ipsilateral side to nerve ligation on days 4, 7 and 14 after nerve ligation in the spinal slices (P < 0.0001). The treatment with i.p. MK-801 suppressed the increases in the contents of glutamate and aspartate and in [Ca2+]i on days 4 and 7. However, the ipsilateral contents of glutamate and aspartate significantly increased on day 14 (P < 0.001 and 0.003, respectively); the increased [Ca2+]i was also observed on day 14 (P < 0.001), and the spatial pattern of the increased regions was similar to untreated CCI rats. We interpret these results to indicate that neuropathic hyperalgesia induced by CCI in the rat is associated with an increase in glutamate and aspartate contents and the subsequent activation of NMDA receptors, followed by an increase in [Ca2+]i within dorsal horn of the spinal cord.

Chemical Interactions between Fibrosarcoma Cancer Cells and Sensory Neurons Contribute to Cancer Pain

“…An increase in basal [Ca 2ϩ ] i in small DRG neurons was noted in neurons isolated from tumor-bearing mice and neurons cocultured with fibrosarcoma cells. A similar change was noted in some models of neuropathic pain (Kawamata and Omote, 1996;Kostyuk et al, 1999). An increase in [Ca 2ϩ ] i can have profound physiological consequences, including activation of Ca 2ϩ / calmodulin-dependent protein kinase (Miller and Kennedy, 1986;Hanson and Schulman, 1992) and protein kinase C (Chen and Huang, 1992), which can increase gene expression at the level of the soma (Seybold et al, 2006) or increase transduction of sensory receptors at the level of the nerve terminal (Regehr et al, 1994).…”

Time-Dependent Cross Talk between Spinal Serotonin 5-HT2AReceptor and mGluR1 Subserves Spinal Hyperexcitability and Neuropathic Pain after Nerve Injury

“…This is suggestive that the activity of mGluR1, which is low or absent in normal physiological conditions (Azkue et al, 2003), may be insufficient to effectively interact with 5-HT 2A R (Aira et al, 2010) but becomes upregulated by 5-HT 2A R after SNL and thus may act as a feedforward activation mechanism for the latter. Increased central glutamate release over the days following nerve injury (Kawamata and Omote, 1996) may additionally contribute to mGluR1 activation, and the lack of contralateral changes in glutamate release (Kawamata and Omote, 1996) is consistent with the milder behavioral and biochemical changes observed here contralaterally.…”

Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy

“…As the afterdischarge in response to innocuous touch stimulation is depressed by an NK-1 receptor antagonist (Pitcher and Henry, 2004), presumably due to blocking the effects of tonic release of substance P (Malcangio et al, 2000), it is tempting to extrapolate from the results of the present study that the gain in excitability of dorsal horn neurons in response to innocuous cutaneous stimulation may also be due to persisting peripheral drive. Thus, persisting hyperalgesia and/or allodynia that occurs following mechanical stimulation in people who suffer neuropathic pain may be due to altered afferent input that is mediated by continuous release of neurotransmitters (Wang et al, 2007) such as glutamate (Cui et al, 1997;Kawamata and Omote, 1996;Somers and Clemente, 2002) and peptide neuromodulators including substance P Ma and Bisby, 1998;Malcangio et al, 2000) and CGRP (Helgren et al, 1999;Lee and Kim, 2007;Ma and Bisby, 1998).…”