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Preoperative stress could delay the recovery of postoperative pain and has been reported to be a risk factor for chronic postsurgical pain. As stress could facilitate the proinflammatory activation of microglia, we hypothesized that these cells may play a vital role in the development of preoperative stress-induced pain chronification after surgery. Our experiments were conducted in a rat model that consists of a single prolonged stress (SPS) procedure and plantar incision. A previous SPS exposure induced anxiety-like behaviors, prolonged incision-induced mechanical allodynia, and potentiated the activation of spinal microglia. Based on the results from ex vivo experiments, spinal microglia isolated from SPS-exposed rats secreted more proinflammatory cytokines upon challenge with LPS. Our results also demonstrated that microglia played a more important role than astrocytes in the initiation of SPS-induced prolongation of postsurgical pain. We further explored the therapeutic potential of agonism of α7 nAChR, an emerging anti-inflammatory target, for SPS-induced prolongation of postsurgical pain. Multiple intrathecal (i.t.) injections of PHA-543613 (an α7 nAChR agonist) or PNU-120596 (a type II positive allosteric modulator) during the perioperative period shortened the duration of postsurgical pain after SPS and suppressed SPS-potentiated microglia activation, but their effects were abolished by pretreatment with methyllycaconitine (an α7 nAChR antagonist; i.t.). Based on the results from ex vivo experiments, the anti-inflammatory effects of PHA-543613 and PNU-120596 may have been achieved by the direct modulation of microglia. In conclusion, stress-induced priming of spinal microglia played a key role in the initiation of preoperative stress-induced prolongation of postsurgical pain, and PHA-543613 and PNU-120596 may be potential candidates for preventing pain chronification after surgery.
Learn More >Sensorimotor cortical activity is altered in both the immediate acute, and chronic stages of musculoskeletal pain. However, these changes are opposite, with decreased cortical activity reported in experimentally-induced acute pain (lasting minutes to hours), and increased cortical activity in chronic, clinical pain (lasting>6 months). It is unknown whether sensorimotor cortical activity is altered in acute, clinical musculoskeletal pain (lasting<4 weeks). In 36 individuals with acute, non-specific, clinical low back pain (LBP) and 36 age- and sex-matched, pain-free controls, we investigated the processing of non-noxious afferent inputs using sensory evoked potentials (SEPs), as well as corticomotor excitability and organisation of the primary motor cortex using transcranial magnetic stimulation. Processing of non-noxious sensory inputs was lower (smaller area of the N-N-P SEP complex) in acute LBP (F=45.28, p<0.01). Examination of specific SEP components revealed smaller area of the N and P SEP components in acute LBP, although inter-individual variability was high. Motor cortical map volume was lower in acute LBP (F=5.61, p=0.02). These findings demonstrate that acute LBP is characterised by lower sensorimotor cortical activity at the group level. However, individual variation was high, suggesting individual adaptation of cortical plasticity in acute pain. Perspective: This is the first study to examine sensorimotor cortical activity in the acute stage of clinical low back pain. This information is critical for understanding the neurophysiology of acute low back pain.
Learn More >Migraine encompasses a broader spectrum of sensory symptoms than just headache. These "other" symptoms, eg, sensory phobias, cognitive and mood changes, allodynia, and many others indicate an altered sensitivity to sensory input which can be measured, in principle, by quantifying sensory threshold changes longitudinally over time. Photophobia, for example, can be quantified by investigating the discomfort thresholds towards the luminance of light. The aim of this review is to look into how thresholds change in patients with migraine. We performed a PubMed search up to June 2018 targeting all peer-reviewed articles evaluating the changes in threshold, sensory phobia, or sensitivity in patients with migraine. Migraineurs, in general, exhibit lower sensory thresholds compared with healthy controls. These threshold changes seem to follow the different phases during a migraine cycle. In general, thresholds reach a nadir when the headache starts (the ictal phase), rise after the headache ends, and then gradually descend towards the next attack. The sensory modality of measurement-mechanical, thermal, or nociceptive-and the location of measurement-trigeminal vs somatic dermatome-also influence the sensory threshold. Functional imaging studies provide evidence that the hypothalamo-thalamo-brainstem network may be the driving force behind the periodic threshold changes. In summary, there is evidence in the literature that migraine could be understood as a periodic sensory dysregulation originating from the brain. Nevertheless, the interstudy discrepancy is still high due to different study designs and a lack of focus on distinct migraine phases. Further well-designed and harmonized studies with an emphasis on the cyclic changes still need to be conducted.
Learn More >Peripheral sensory neurons express multiple voltage-gated sodium channels (Na ) critical for the initiation and propagation of action potentials and transmission of sensory input. Three pore-forming sodium channel isoforms are primarily expressed in the peripheral nervous system (PNS): Na 1.7, Na 1.8 and Na 1.9. These sodium channels have been implicated in painful and painless channelopathies and there has been intense interest in them as potential therapeutic targets in human pain. Emerging evidence suggests Na 1.6 channels are an important isoform in pain sensing. This study aimed to assess, using pharmacological approaches, the function of Na 1.6 channels in peripheral sensory neurons. The potent and Na 1.6 selective β-scorpion toxin Cn2 was used to assess the effect of Na 1.6 channel activation in the PNS. The multidisciplinary approach included; Ca imaging, whole-cell patch-clamp recordings, skin- and gut-nerve preparations and in vivo behavioural assessment of pain behaviours. Cn2 facilitates Na 1.6 early channel opening, increased persistent and resurgent currents in large diameter DRG neurons. This promotes enhanced excitatory drive and tonic action potential firing in these neurons. In addition, Na 1.6 channel activation in the skin and gut leads to increased response to mechanical stimuli. Finally, intra-plantar injection of Cn2 causes mechanical but not thermal allodynia. This study confirms selectivity of Cn2 on Na 1.6 channels in sensory neurons. Activation of Na 1.6 channels, in terminals of the skin and viscera, leads to profound changes in neuronal responses to mechanical stimuli. In conclusion, sensory neurons expressing Na 1.6 are important for the transduction of mechanical information in sensory afferents innervating the skin and viscera. This article is protected by copyright. All rights reserved.
Learn More >Orofacial inflammation could activate satellite glial cells (SGCs) in the trigeminal ganglion (TG) to produce interleukin 1β (IL-1β) which plays crucial roles in the development of inflammatory pain. Recent studies have shown that gamma-amino butyric acid-B (GABA) receptor could modulate the expression of inflammatory cytokines in microglia and astrocytes in the spinal cord. The objective of this study was to investigate whether GABA receptors in TG SGCs attenuate inflammatory facial pain via mediating IL-1β following inflammation and its mechanisms. Complete Freund's adjuvant (CFA) was injected into the whisker pad of rats to induce inflammation in vivo. Lipopolysaccharide (LPS) was added to culture medium to activate SGCs in vitro. Behavioral measures showed that microinjection of baclofen (a selective GABA receptor agonist) into the TG ameliorated the mechanical allodynia of CFA-treated rats. Interestingly, baclofen pretreatment inhibited SGC activation and IL-1β production, however, preserved the decreased expression of GABA receptors in SGCs activated by CFA in vivo and LPS in vitro. In addition, baclofen suppressed the increased expression of p-NF- κ B p65, p-I κ Bα, and p-p38 MAPK, while reversed the decreased production of I κ Bα, and further enhanced the increased expression of p-ERK(1/2) in LPS-treated SGCs in vitro. Finally, those effects of baclofen were abolished by saclofen (a specific GABA receptor antagonist) co-administration. Altogether, these results demonstrated for the first time that activation of GABA receptor might inhibit IL-1β production by suppressing NF- κ B and p38 MAPK signaling pathway activation and restore GABA receptor expression in SGCs to attenuate inflammatory facial pain.
Learn More >To explore the role of large-artery atherosclerosis in migraine, we investigated the association between migraine and arterial calcification in different intracranial and extracranial vessels.
Learn More >Up to 30% of patients experience persistent pain and functional limitations following total knee replacement (TKR). Rapid symptom relief in the early postoperative period may be linked to longer-term outcome improvements. We sought to identify early improvement trajectories and to identify risk factors for suboptimal outcomes.
Learn More >Around 20% of patients undergoing surgery for lumbar radiculopathy develop chronic pain after surgery, leading to high socioeconomic burden. Current perioperative interventions, including education and rehabilitation, are not always effective in preventing prolonged or chronic postoperative pain and disability. Here, a shift in educational intervention from a biomedical towards a biopsychosocial approach for people scheduled for lumbar surgery is proposed. Pain neuroscience education (PNE) is a biopsychosocial approach that aims to decrease the threat value of pain by reconceptualizing pain and increasing the patient's knowledge about pain. This paper provides a clinical perspective for the provision of perioperative PNE, specifically developed for patients undergoing surgery for lumbar radiculopathy. Besides the general goals of PNE, perioperative PNE aims to prepare the patient for postsurgical pain and how to cope with it.
Learn More >Post-traumatic injury pain is commonly treated with oral nonsteroidal anti-inflammatory drugs (NSAIDs). However, oral NSAIDs causes several adverse events, with topical formulations arising as an important alternative. Therefore, we aimed to evaluate the efficacy and safety of loxoprofen patch in the treatment of patients with post-traumatic pain. This phase III, randomized, double-blind, non-inferiority study enrolled Brazilian patients aged 18-65 years diagnosed with lower and upper limbs post-traumatic injury who were experiencing moderate or severe pain. Patients were assigned to active loxoprofen patch (LX-P) or to loxoprofen tablet (LX-T) and pain intensity was measured based on a Visual Analog Scale (VAS) score variation after seven days of treatment. Data on clinical symptoms, rescue medication use, and adverse events were also collected. VAS score variation was compared using a 10% non-inferiority margin. Two hundred and forty-two patients were randomly assigned to the LX-P (n=123) or to LX-T (n=119). The results showed a reduction in pain after seven days of treatment: -49.96 (n=118; SE 1.7) in the LX-P and -47.71 (n=117; SE 1.6) in the LX-T groups (difference of -2.25; 95% CI: -5.97 – 1.47; p=0.23). On the safety analysis, LX-T group presented twice as many patients with treatment-emergent adverse events as the LX-P group (30.8% and 14.2%, respectively). A sensitivity analysis demonstrated that rescue medication use has not affected the primary endpoint. This study showed that LX-P has a comparable efficacy to LX-T, but with a better safety profile, being a therapeutic option for the treatment of post-traumatic injury pain.
Learn More >Most studies fail to show an association between higher levels of pain-related fear and protective movement behavior in patients with chronic low back pain (CLBP). This may be explained by the fact that only general measures of pain-related fear have been used to examine the association with movement patterns. This study explored whether task-specific, instead of general measures of pain-related fear can predict movement behavior.
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