Evaluation of Postsurgical Hyperalgesia and Sensitization After Open Inguinal Hernia Repair: A Useful Model for Neuropathic Pain?

Cutaneous mechanical hyperalgesia can be induced in healthy volunteers in early phase analgesic studies to model central sensitization, a key mechanism of persistent pain. However, such hyperalgesia is short-lived (a matter of hours), and is used only for assessing only single drug doses. In contrast, postsurgical peri-incisional hyperalgesia may be more persistent and hence be a more useful model for the assessment of the efficacy of new analgesics. We undertook quantitative sensory testing in 18 patients at peri-incisional and nonoperated sites before open inguinal hernia repair and up to the 24th postsurgical week. The spatial extent of punctate hyperalgesia and brush allodynia at the peri-incisional site were greatest at weeks 2 and 4, but had resolved by week 24. Heat allodynia, suggestive of local inflammation or peripheral sensitization, was not observed; instead, there were deficits in cold and heat sensory detection that persisted until week 24. The findings suggest that central sensitization contributes significantly to mechanical hyperalgesia at the peri-incisional site. The prolonged duration of hyperalgesia would be advantageous as a pain model, but there was considerable variability of mechanical hyperalgesia in the cohort; the challenges of recruitment may limit its use to small, early phase analgesic studies. PERSPECTIVE: Peri-incisional mechanical hyperalgesia persists for ≥4 weeks after open inguinal hernia repair and reflects central sensitization; this may have usefulness as a model of chronic pain to assess the potential of antineuropathic analgesics.Unrestricted educational grant from GlaxoSmithKline U

Colocalized Structural and Functional Changes in the Cortex of Patients with Trigeminal Neuropathic Pain

Background: Recent data suggests that in chronic pain there are changes in gray matter consistent with decreased brain volume, indicating that the disease process may produce morphological changes in the brains of those affected. However, no study has evaluated cortical thickness in relation to specific functional changes in evoked pain. In this study we sought to investigate structural (gray matter thickness) and functional (blood oxygenation dependent level – BOLD) changes in cortical regions of precisely matched patients with chronic trigeminal neuropathic pain (TNP) affecting the right maxillary (V2) division of the trigeminal nerve. The model has a number of advantages including the evaluation of specific changes that can be mapped to known somatotopic anatomy. Methodology/Principal Findings: Cortical regions were chosen based on sensory (Somatosensory cortex (SI and SII), motor (MI) and posterior insula), or emotional (DLPFC, Frontal, Anterior Insula, Cingulate) processing of pain. Both structural and functional (to brush-induced allodynia) scans were obtained and averaged from two different imaging sessions separated by 2–6 months in all patients. Age and gender-matched healthy controls were also scanned twice for cortical thickness measurement. Changes in cortical thickness of TNP patients were frequently colocalized and correlated with functional allodynic activations, and included both cortical thickening and thinning in sensorimotor regions, and predominantly thinning in emotional regions. Conclusions: Overall, such patterns of cortical thickness suggest a dynamic functionally-driven plasticity of the brain. These structural changes, which correlated with the pain duration, age-at-onset, pain intensity and cortical activity, may be specific targets for evaluating therapeutic interventions

Fifth European Dirofilaria and Angiostrongylus Days (FiEDAD) 2016

Peer reviewe

Coupling of sympathetic and somatic motor outflows from the spinal cord in a perfused preparation of adult mouse in vitro

The relationship between sympathetic and somatic motor outflows from thoraco-lumbar spinal cord was investigated in a novel arterially perfused trunk-hindquarters preparation of adult mouse.Ongoing activity was present in both somatic motor (obturator, sciatic or femoral nerves) and sympathetic outflows (either renal nerve or abdominal sympathetic chain). Sympathetic activity was rhythmic with bursts frequencies of 0.6–2.2 Hz. No obvious rhythmic activity was found in the somatic motor outflow. There were periods during which sympathetic and somatic motor activity were correlated.Addition of NMDA (20–80 μM) to the perfusate elicited repetitive burst discharges in the somatic motor outflow which were sometimes rhythmic. The frequency of these burst discharges/rhythmic activity varied between preparations but in all cases increased with increasing NMDA concentration.NMDA induced burst discharges in the sympathetic outflow. This bursting activity was of the same frequency as the somatic motor outflow and the two were coupled as revealed by correlation analysis. Periods of coupling persisted for up to 3 min.Administration of hexamethonium (300 μM), to block sympathetic ganglionic transmission, had no effect on the somatic motor activity but severely attenuated sympathetic nerve discharge.The thoraco-sacral cord therefore has the neuronal machinery necessary for generating and coupling activity in somatic motor and sympathetic outflows. Our findings indicate a dynamic control over the degree of coupling. We discuss that the synchronization of these neural outflows reflects either coupling between two independent mechanisms or the presence of a common synaptic driver impinging on both somatic motor and sympathetic neurones

Homotopic stimulation can reduce the area of allodynia in patients with neuropathic pain

Allodynia is a common, troublesome feature of neuropathic pain conditions. In a previous study of postherpetic neuralgia we observed that repeated tactile stimulation appeared to reduce the size of the area of allodynia in some patients. We have undertaken a pragmatic clinical study to characterise this phenomenon in neuropathic pain patients with a range of different aetiologies. Neuropathic pain patients with a discrete area of tactile allodynia were recruited (n=20). We assessed the sensitive area using punctate and dynamic tactile stimuli, and thermal quantitative sensory testing. On two separate testing visits, the patients had repeated (10x over 1 min) noxious heat or cotton bud strokes applied to the affected site or contralaterally. Tactile stimulation of the affected area evoked pain (median 7 NRS) and a reduction (>30%) in the area of allodynia in 9/18 patients (maximum -48+/-9%, after 20 min), although the intensity of allodynic pain was unchanged. This effect persisted for over 1h and was present the following day in all patients tested (n=5/5). No subjects showed an increase in area after allodynic stimulation. There was no change in heat pain threshold at a distant site following allodynic stimulation, suggesting no activation of diffuse noxious inhibitory control. Repeated thermal noxious stimulation (median NRS 7) could also elicit changes (>30%) in the area of allodynia in some patients (reductions in 7/20, increases in 3/20). Thus, we have found that a brief period of homotopic painful stimulation can reduce the area of allodynia in around half of patients with established neuropathic pains