Spread of excitation across modality borders in spinal dorsal horn of neuropathic rats

Abstract

Under physiological conditions, nociceptive information is mainly processed in superficial laminae of the spinal dorsal horn, whereas non-nociceptive information is processed in deeper laminae. Neuropathic pain patients often suffer from touch-evoked pain (allodynia), suggesting that modality borders are disrupted in their nervous system. We studied whether excitation evoked in deep dorsal horn neurons either via stimulation of primary afferent Abeta-fibres, by direct electrical stimulation or via glutamate microinjection leads to activation of neurons in the superficial dorsal horn. We used Ca(2+)-imaging in transversal spinal cord slices of neuropathic and control animals to monitor spread of excitation from the deep to the superficial spinal dorsal horn. In neuropathic but not control animals, a spread of excitation occurred from the deep to the superficial dorsal horn. The spread of excitation was synaptically mediated as it was blocked by the AMPA receptor antagonist CNQX. In contrast, block of NMDA receptors was ineffective. In control animals, the violation of modality borders could be reproduced by bath application of GABA(A) and glycine receptor antagonists. Furthermore, we could show that neuropathic animals were more prone to synchronous network activity than control animals. Thus, following peripheral nerve injury, excitation generated in dorsal horn areas which process non-nociceptive information can invade superficial dorsal horn areas which normally receive nociceptive input. This may be a spinal mechanism of touch-evoked pain.

Electrophysiological properties of spinal wide dynamic range neurons in neuropathic pain rats following spinal nerve ligation

“…In neuropathic pain animals, the dorsal horn network is shown to be more prone to synchronous network activity compared with that in normal control animals [27] . Simultaneous activation of many adjacent neurons after a light intensity of stimulation could lead to greater additive responses transmitted supraspinally, therefore further amplifying the effect of the receptive field enlargement.…”

Lamina specific loss of inhibition may lead to distinct neuropathic manifestations: a computational modeling approach

“…Thus, we chose β Lamina_I > β Lamina_II > β Deeper_Laminae . From the results obtained by the groups of Baba et al (1999), Cain et al (2001) and Schoffnegger et al (2008), it can be seen that threshold Aδ ≈ 2 threshold Aβ and threshold C ≈ 10 threshold Aβ . We selected threshold Aβ = 2.1 mN (Cain et al, 2001) to find threshold Aδ and threshold C and the corresponding normalized values were used to set the parameter umbr for each Neuroid representing a specific primary afferent type.…”

“…The latter is possible by adjusting two additional parameters: K r , a dimensionless proportionality constant to control the amplitude of the output, and maxcount, a time parameter to extend the output signal by several milliseconds after the last spike before dropping to the resting value. Several studies have quantified the response properties of different types of neurons to depolarizing/ hyperpolarizing current injections as well as to mechanical/thermal stimuli using both in vitro and in vivo preparations (Baba et al, 1999;Cain et al, 2001;Graham et al, 2004;Ruscheweyh and Sandkühler, 2002;Schoffnegger et al, 2008;Slugg et al, 2000;2004). Based on the available experimental evidence, functional features of primary afferent fibers and dorsal horn neurons have been pointed out as follows:…”

“…Aβ-fibers and C-fibers exhibit the lowest and the highest median activation thresholds, respectively, in response to both current injections (Baba et al, 1999;Schoffnegger et al, 2008) and mechanical stimuli (Cain et al, 2001) (i.e., threshold Aβ < threshold Aδ < threshold C ); however, some studies have reported that threshold C < threshold Aδ when forced-controlled stimulation protocols were used (Slugg et al, 2000;2004).…”

Behavioral Models of Pain States Evoked by Physical Injury to the Peripheral Nerve

“…4 Injury produces alterations in dorsal horn excitability, leading to lowered thresholds in dorsal horn neurons and increases in their receptive field size. 5 Several mechanisms have been identified that are believed to underlie these changes.…”