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Current Research
The neural substrates of the association between neuropathic pain and negative affect
Neuropathic pain is often associated with debilitating emotional co-morbidities such as anxiety and depression. This project is part of a wider portfolio of animal and patient studies attempting to elucidate the link between neuropathic pain and affective disorders. This started with our recent work which demonstrated that correlates of such negative affect can be observed in a range of animal models of peripheral neuropathy. The aim of this project is to elucidate the neuroanatomical and biochemical basis of this link between neuropathic pain and negative affect at a brain level. A separate parallel project is investigating the role of spinal afferent pathways in driving these behaviours. Ultimately, we hope this strategy will reveal drug development strategies for novel treatments of these co-morbidities.
Our initial studies will target the amygdala as a key centre in neuropathic pain related anxiety. There is strong evidence of the involvement of the amygdala in the interactions between pain and emotion since it is one of the supraspinal centres involved in processing pain (it receives nociceptive inputs from the spinal cord, including via the parabrachial nucleus) and it is the centre that coordinates the motor, endocrine and vegetative components of the anxiety-fear responses (through its descending projections). Moreover, the amygdala is also involved in the emotional targeting of afferent stimuli (see Figure). Some innate aversive stimuli accede to the amygdala which generates emotional responses (fear/anxiety/aversion) against these stimuli. If there is a coincidence in the presentation of these innately aversive stimuli with neutral ones in the amygdala, a learned response can be generated and these former neutral stimuli can elicit, by themselves, an emotional response. Therefore, after the initial association, the neutral stimuli acquire a negative connotation and consequently, can provoke the negative experience. This system has a strong adaptive value since “predictor stimuli” allow us to avoid threatening situations, but if a perturbation in this system occurs, like those present in neuropathies where the nociceptive stimulus is always present, we can observe imbalances which lead to an over-expression of anxiety and therefore to an emotional dysfunction.
Our experimental approach will elucidate the role of discreet regions of the amygdala in driving the anxiety-like and depression-like behaviours which we have previously documented in animal models of neuropathic pain. Initially, we will employ stereotactic lesions of/microinjections into specific amygdaloid centres and determine the influence of such techniques in perturbing the expression of these behaviours in neuropathic rats. We will also study the activation of brain regions in neuropathic rodents by measuring the expression of c-Fos and related proteins and correlating this with the extent of affective behaviours observed in individual animals. Additionally, we intend to compare these animal findings with human functional brain imaging data from extensively phenotyped patients with peripheral neuropathies recruited from our clinics. Finally, we will perform gene microarray analysis of brain regions of interest (as revealed by the above approach) and then proceed to validate selected targets using a range of conventional biochemical and pharmacological approaches, as well as novel techniques available within the LPC such as RNA interference.

Background references:

(1) Hasnie FS et al. Further characterization of a rat model of varicella zoster virus-associated pain: Relationship between mechanical hypersensitivity and anxiety-related behavior, and the influence of analgesic drugs. Neuroscience 2007;144(4):1495-508.

(2) Maratou K et al. Comparison of dorsal root ganglion gene expression in rat models of traumatic and HIV-associated neuropathic pain. Eur J Pain 2009;13 (387):398.

(3) Segerdahl AR et al. Fear-avoidance behaviour in rat models of neuropathic pain: 2 chamber light-dark box paradiagm. Soc.Neurosci.Abstr. 186.20. 2007.

(4) Wallace VCJ et al. The effect of the palmitoylethanolamide analogue, palmitoylallylamide (L-29) on pain behaviour in rodent models of neuropathy. Br J Pharmacol 2007;151(7):1117-28.

(5) Wallace VCJ et al. Anxiety-like behaviour is attenuated by gabapentin, morphine, diazepam in a rodent model of HIV anti-retroviral associated neuropathic pain. Neuroscience Letters 2008;448:153-156.

(6) Wallace VCJ et al. Characterisation of rodent models of HIV-gp120 and anti-retroviral associated neuropathic pain. Brain 2007;130(10):2688-702.

(7) Wallace VCJ et al. Pharmacological, behavioural and mechanistic analysis of HIV-1 gp120 induced painful neuropathy. Pain 2007;133(1-3):47-63.