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In this edition of the journal, Borges et al. (2012) presented neuroanatomical data from their laboratory studies identifying patterns of supra-spinal adaptation in response to peripheral nerve injury as well as nociceptor activation in neuropathic and non-neuropathic rats. This approach attempts to unravel the different neural ‘signatures’, which may underlie the expression of ongoing versus evoked pain in the neuropathic condition.

Using a relatively recent and technically reliable approach, neurons and glia that undergo an adaptive response to tissue damaging, nociceptor activating and/or pain-evoking events are detected histologically by identifying the phosphorylated forms of intracellular signal transduction molecules such as those represented in the mitogen-activated protein kinase family. In this case, the immunohistochemical identification of phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK 1/2) (White et al., 2011). In earlier studies, this approach has revealed neurons of the dorsal root ganglia and spinal cord undergoing transcription-dependent and transcription-independent changes critical for central sensitization, leading to sensory hypersensitivity (pain). The authors call attention to the fact that a major focus on dorsal root ganglia and the spinal cord segments receiving their central projections has left the question of supra-spinal adaptations in response to nerve injury and noxious stimulation relatively unexplored territory. The authors highlight that this is despite the fact that it is broadly accepted that supra-spinal adaptations occur, and that they are (1) likely to underlie, in part, the sensory hypersensitivity/pain and (2) may contribute to the expression of the complex physiological and behavioural changes, which characterize most pain states. Similar to discussions in the early reports of c-fos/Fos mapping as a functional marker of pain pathways, a significant challenge and ethical consideration in this type of experiment is the decision of whether or not to use anaesthesia. Investigators often report making this decision with the aim of controlling for ‘unwanted variables’ in the response to noxious stimuli, which is a point worth considering further. Given that the International Association for the Study of Pain taxonomy defines pain as ‘both a sensory and emotional experience’, and that emotion in its broadest sense encompasses autonomic, endocrine and motor/behavioural responses, the activity patterns and responses modified by anaesthesia are probably as important a response to nerve damage and noxious stimuli as the altered sensation. Notwithstanding the implications of this particular viewpoint, Borges et al. showed very clearly in their report the effects of noxious hind-paw stimulation, under conditions of mononeuropathy versus the non-neuropathic state, in rats anaesthetized with the hypnotic compound, chloral hydrate.

They revealed that 7 days after a nerve injury, phosphorylated ERK1/2 levels in neurons of sciatic recipient segments of the spinal cord do not differ from those in uninjured rats. Furthermore, they reported that noxious hind-paw stimulation only triggers adaptation in neurons of spinal lamina I and II of un-injured rats. This is an interesting observation, which might suggest that these populations of neurons in mononeuropathic rats have reached a ceiling of adaptation. In contrast to spinal cord, nerve injury evoked adaptations (increased pERK expression) in the A5 and A7 noradrenergic cells. The picture in the A6 cells forming the locus coeruleus was, however, more complex. Nerve injury decreased pERK expression in the locus coeruleus. Further, the previously reported increase in neuronal activity of locus coeruleus neurons following acute noxious somatic stimuli in anaesthetized rats with neuropathy (Viisanen and Pertovaara, 2007) did not trigger pERK 1/2-mediated adaptive changes. In non-neuropathic rats in the un-anaesthetized state, acute noxious stimuli are reported to increase pERK expression in locus neurons (Imbe et al., 2009), whereas under anaesthesia, Borges et al. reported no changes. These differences reveal important insights about the effects of anaesthesia on supra-spinal adaptation in these different pain states.

In the brainstem raphe sub-nuclei, the chronic constriction injury was associated with increased pERK expression. Increased pERK in the raphe magnus is also reported following spared nerve injury, which has been shown very convincingly to contribute to the increased sensitivity to mechanical stimuli and to depend on lamina I and II inputs (Geranton et al., 2010). The expression of pERK1/2 was selectively decreased in the raphe obscurus by acute noxious stimulation in rats with mononeuropathy, which stood in contrast to their non-neuropathic counterparts in which it was increased.

Overall, this study highlights very well the anatomically specific effects of neuropathic injury on brainstem adaptation (as determined by pERK1/2 expression); it also highlights distinct anatomical differences in adaptation to acute noxious stimuli in the neuropathic condition. Moreover, by selecting the anaesthetized model, they have also revealed brainstem sites at which their chosen anaesthetic agent likely acts to minimize and possibly abolish unwanted autonomic, endocrine and motor/behavioural responses.

Footnotes
  1. Conflicts of interest

    None declared.

References

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  2. References
  • Borges, G.S., Berrocosod, E., Ortega-Alvaroc, A., Mico, J.A., Netoa, F.L. (2012). Extracellular signal-regulated kinase activation in the chronic constriction injury model of neuropathic pain in anesthetized rats. Eur J Pain 17, 3545.
  • Geranton, S.M., Tochiki, K.K., Chiu, W.W.Y., Stuart, S.A., Hunt, S.P. (2010). Injury induced activation of extra-cellular signal-related kinase (ERK) in the rat rostral ventromedial medulla (RVM) is age dependant and requires the lamina I projection pathway. Mol Pain 6, 5462.
  • Imbe, H., Okamoto, K., Donishi, T., Kawai, S., Enoki, K., Senba, E., Kimura, A. (2009). Activation of ERK in locus coeruleus following acute noxious stimulation. Brain Res 1263, 5057.
  • Viisanen, H., Pertovaara, A. (2007). Influence of peripheral nerve injury on response properties of locus coeruleus neurons and coeruleospinal antinociception in the rat. Neuroscience 146, 17851794.
  • White, J.P.M., Cibelli, M., Fidalgo, A.R., Nagy, I. (2011). Extracellular signal-related kinases in pain of peripheral origin. Eur J Pharmacol 650, 817.