Plasticity of the pain control system induced by neuropathic pain: the amygdala-medulla system

Pain is a multidimensional experience with sensory-discriminative and motivational-affective dimensions. Neuropathic pain is caused by a primary lesion or dysfunction of the nervous tissue that leads to an anomalous nociceptive processing in pain centers. It results from a process of peripheral and central sensitization and is characterized by prolonged hyperalgesia, allodynia and spontaneous pain. The maintenance of these nerve injury-induced symptoms depends on abnormal discharge from peripheral nerves and pronociceptive changes in spinal and supraspinal mechanisms mediating and modulating pain-related signals. The aims of this work were: first, to elucidate what is the relative contribution of rostroventromedial medulla (RVM) ON- and OFF-cells to hypersensitivity observed in neuropathic pain; second, to evaluate if emotional disturbances and structural alterations in the amygdala (AMY) observed in human patients, were produced when inducing neuropathic pain to rats; third, to determine if structural alterations of the amygdala, associated to the peripheral nerve injury, influences RVM regulation of nociception; and finally, to analyze the alterations in response properties of amygdala nociceptive neurons to peripherally-evoked stimulation and what is the cortical influence in the neuropathic process. In this work, we provide evidence that reinforce data indicating that RVM ON-cells are the main responsible for neuropathic hypersensitivity. Although both ON- and OFF- RVM cells were found to respond significantly more in neuropathic animals at a basal state, only ON-cell response was significantly different from Sham animals following noxious and non-noxious stimulation. The peripheral stimuli applied were: tail pinch and cold, since clinical studies indicate that hypersensitivity to these somatic stimuli are frequent after traumatic nerve injuries; and colo-rectal distention (CRD), because not much is known about the influence of somatic neuropathy on visceral processing. As RVM ON-cells are considered to be pronociceptive, they should have a major contribution in the hypersensitivity to peripheral stimulation observed in neuropathic animals. We have demonstrated, for the first time, that animals with a peripheral neuropathy show depressive-like behaviour associated to AMY neuroplasticity. Importantly, AMY structural changes are mediated, at least in part, by an increase in the number of neurons, as a result of cell proliferation. Besides depressive-like behaviour, we also observed an increase in affective painrelated behaviour in neuropathic animals, assessed through the aversive place-conditioning test, which reinforces the association between prolonged neuropathic pain and altered emotional behaviour. Moreover, emotional pain-related behaviour increased after AMY administration of a metabotropic glutamate receptor 1 and 5 (mGluR1/5) agonist and decrease after the local injection of a metabotropic glutamate receptor 1 (mGluR1) antagonist. The AMY administration of an mGluR1/5 agonist has also induced an increase in the discharge rate of ON-cells in the RVM of nerve-injured animals, which was mainly due to the activation of mGluR1. In what concerns the activity of AMY neurons, plastic alterations were present after neuropathy, with an increased spontaneous activity and a general decrease after peripheral stimulation. When evaluating the cortical influence upon nociceptive behaviour of the neuropathic rat, the injection of glutamate (Glu) and of an NMDA-receptor (NMDA-r) antagonist in the rostral anterior cingulate cortex (rACC) produced, respectively, an increase and a decrease in affective painrelated behaviour. When evaluating AMY neuronal discharge rate after the injection of the same reported drugs in the ACC, only glutamate had a significant effect, inducing an increase of AMY neuronal activity. The set of studies performed for this thesis allowed the following conclusions: I) the activity of both RVM ON- and OFF-cells in neuropathic animals is altered towards promoting pronociception, but only ON-cell type appears to be a major role in the increased hypersensitivity observed; II) the structural plasticity observed in the AMY of nerve-injured animals - increased AMY volume as a result of local newborn neurons – is paralleled with the development of depressive-like behaviour; III) emotional pain-related behaviour in neuropathic animals is dependent, at least in part, on the activation of mGluR1/5 in the AMY and of NMDAr in the ACC; IV) the activation of mGluR1 in the AMY of neuropathic animals causes an increase in the activity of pronociceptive RVM ON-cells.

Name thesis:degree_name

Tese de doutoramento em Ciências da Saúde (ramo de conhecimento em Ciências Biológicas e Biomédicas)

Year dc:date.issued

2009

Author dc:creator

• Gonçalves, Leonor

Advisors dc:contributor.advisor

• Almeida, Armando
• Pertovaara, Antti

Statement dc:rights

• openAccess

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/1822/9477

OAI record oai:identifier

http://repositorium.sdum.uminho.pt/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Arepositorium.uminho.pt%3A1822%2F9477