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My research objectives are:


1. To understand the neural basis of sensory biomarkers for pain modulation, and to improve the translatability of pre-clinical measures by aligning paradigms in parallel rodent and human studies.

 

and

 

2. To identify the neural circuits that mediate the reciprocal interaction between chronic pain and co-morbid mood disorders.

I utilise in vivo electrophysiology to record from deep dorsal horn wide dynamic range neurones within the spinothalamic pathway. Unlike paw withdrawal reflexes which only provide limited insight into response thresholds, neuronal recordings provide a wealth of information about how sensory inputs are processed at the spinal level. These recordings permit the study of: (1) a full stimulus-response relationship and intensity dependent coding, (2) spatial summation, (3) temporal summation (see video below), (4) encoding of stimulus modality, (5) after-firing, (6) local and descending modulation of spinal output, and (7) post-synaptic responses to convergent Aβ, Aδ and C afferent input. These characteristics are conserved across species and single unit recordings have also been obtained from the sensory thalamus of patients undergoing stereotaxic procedures for other conditions. From these we can see that polymodal neurones exist that encode sensory modalities and stimulus intensity, but micro-stimulation at these recording sites also elicit natural sensations in the region of the receptive fields.

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WIND-UP

An example of wind-up in the mouse deep dorsal horn.  A train of 16 electrical stimuli are delivered at 3x the threshold for activating C-fibres at a frequency of 0.5 Hz.

Note the progressive increase in excitability following repetitive stimulation and the prolonged post-discharges towards the end of the train. Wind-up has been interpreted as the capacity to amplify nociceptive signals and shares many features with central sensitisation.

Windup

Trendafilova et al., Sodium-Calcium Exchanger-3 Regulates Pain ‘Wind-Up’: From Human Psychophysics to Spinal Mechanisms. Neuron 2022; 110(16):2571-2587.e13 10.1016/j.neuron.2022.05.017

TEMPORAL SUMMATION OF PAIN

Temporal summation of pain describes a perceptual response where repeated low frequency stimulation with a noxious stimulus results in a progressive increase in the perceived pain intensity. Neuronal wind-up in the dorsal horn (above) is thought to represent the spinal neuronal substrate for this perceptual phenomenon. Wind-up is a form of short term neuronal plasticity which generates features of neuronal sensitisation reminiscent of central sensitisation (a longer term form of synaptic plasticity). Temporal summation of pain is frequently interpreted as the capacity to amplify nociceptive inputs and may have value as a sensory biomarker for endogenous pain modulation. Drugs that are capable of inhibiting neuronal wind-up in rodent models may benefit patients with exacerbated temporal summation (e.g. ketamine). Studying temporal summation of pain and wind-up can also aid the identification of novel drug targets, as was the case with NCX3.

DNIC
DIFFUSE NOXIOUS INHIBITORY CONTROLS
Figure 2.tiff

In rats, DNIC can be recruited by applying a distant heterotopic noxious stimulus. While recording from wide dynamic range spinal neurones under anaesthesia, a noxious von Frey (60g) is applied to the hind paw and the response quantified. This is then repeated with a clamp applied to the ear (CS – conditioning stimulus). In the sham animals, we can see that DNIC are active and reduces the neuronal response. The effect of this concurrent 10s conditioning is quite short lived and we can see the response returns to normal within a minute (and the test can be repeated). In the neuropathic animals (SNL), the ear clamp no longer has the same effect and DNIC are absent.

CONDITIONED PAIN MODULATION

Conditioned pain modulation (CPM) is a test based on the knowledge that 'pain inhibits pain.' Applying two distant noxious stimuli recruits top-down inhibitory signalling pathways that supress the perceived pain intensity of the applied stimuli. Diffuse noxious inhibitory controls (DNIC) are the analogous process in rodents and are considered the key neural basis of CPM (see above). However, with CPM there are many other considerations as the subject will be influenced by cognitive factors such as stress, anticipation, expectation etc, hence the distinction between CPM and DNIC. The absence of CPM in many neuropathic patients is hypothesised to represent reduced descending inhibitory signalling and this can be restored in these patients by drugs that block noradrenaline reuptake (e.g. duloxetine and tapentadol). These studies have been successfully back-translated; DNIC can be restored in neuropathic animals by tapentadol and reboxetine (NRI), but reducing facilitatory drive alone can also restore DNIC. These findings suggest that targeting mechanisms/pathways that reduce descending facilitation and/or augment descending inhibition can restore DNIC (and presumably CPM).

CPM.jpg
OFFSET HYPOEXCITABILITY / ONSET HYPEREXCITABILITY
OA_OH.tiff

Central modulatory mechanisms may be recruited when the stimulus intensity fluctuates over time. Single unit recordings of wide dynamic range neurones were obtained from the rat deep dorsal horn. (A) Compared to a constant temperature ramp at 47°C, a transient increase in stimulus intensity of 1°C (T2) produced a decrease in neuronal firing following stimulus offset (T3). (B) When applying an inverted temperature ramp, a transient decrease in stimulus intensity of 1°C (T2) produced an increase in neuronal firing following stimulus onset (T3).

OA_OH qst.tif
OFFSET ANALGESIA /
ONSET HYPERALGESIA

Offset analgesia is evoked by applying constant heat ramps with a transient 1°C increase in temperature inserted and is proposed to recruit central inhibitory mechanisms upon stimulus offset resulting in a paradoxical decrease in perceived pain intensity, and intriguingly this sensory phenomenon is bidirectional as inversion of the temperature ramp can produce a paradoxical hyperalgesia following stimulus onset. Several independent groups have reported an absence of offset analgesia in people living with chronic or neuropathic pain potentially indicating a loss of endogenous pain modulation, however without precise mechanistic insights the interpretation of this observation is severely limited. My research aims to identify the neural basis of this perceptual phenomenon.

LATERAL HABENULA CIRCUITS FOR THE REGULATION OF PAIN AND MOOD

The lateral habenula has long been at the centre of theories linking chronic pain and depression. Habenula hyperactivity has been implicated in numerous psychiatric conditions either indirectly from neuroimaging studies or directly from neuromodulation case studies. The lateral habenula is also proposed as a crucial site of action for the rapid anti-depressant effect of ketamine. As part of its function in encoding aversive states, the lateral habenula is implicated in signalling pain and analgesia. Using viral tracing methods, behaviour and in vivo electrophysiology, I am investigating the role of lateral habenula efferent pathways in regulating mood and the transmission of pain via the descending pain modulatory system in a chronic pain state.

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