Pain
-
Mechanisms of visceral pain sensitization and referred somatic hypersensitivity remain unclear. We conducted calcium imaging in Pirt-GCaMP6s mice to gauge responses of dorsal root ganglion (DRG) neurons to visceral and somatic stimulation in vivo. Intracolonic instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) induced colonic inflammation and increased the percentage of L6 DRG neurons that responded to colorectal distension above that of controls at day 7. ⋯ Visceral irritation from intracolonic capsaicin instillation also increased Evans blue extravasation in hind paws and low-back skin and acutely increased the percentage of L4 DRG neurons responding to hind paw pinch and the response of L6 DRG neurons to low-back brush stimulation. These findings suggest that TNBS-induced colitis and capsaicin-induced visceral irritation may sensitize L6 DRG neurons to colorectal and somatic inputs and also increase the excitability of L4 DRG neurons that do not receive colorectal inputs. These changes may represent a potential peripheral neuronal mechanism for visceral pain sensitization and referred somatic hypersensitivity.
-
Peripheral denervation and pain are hallmarks of small fiber neuropathy (SFN). We investigated the contribution of skin cells on nociceptor degeneration and sensitization. We recruited 56 patients with SFN and 31 healthy controls and collected skin punch biopsies for immunohistochemical and immunocytochemical analysis of netrin-1 (NTN1) and proinflammatory and anti-inflammatory cytokine expression patterns. ⋯ In the naive state, keratinocytes of patients with SFN show a higher expression of transforming growth factor-β1 (P < 0.05), while fibroblasts display higher expression of the algesic cytokines interleukin (IL)-6 (P < 0.01) and IL-8 (P < 0.05). IL-6 incubation of murine DRG neurons leads to an increase in action potential firing rates compared with baseline (P < 0.01). Our data provide evidence for a differential effect of keratinocytes and fibroblasts on nociceptor degeneration and sensitization in SFN compared with healthy controls and further supports the concept of cutaneous nociception.
-
The voltage-gated sodium channel Nav1.7 is highly expressed in nociceptive afferents and is critically involved in pain signal transmission. Nav1.7 is a genetically validated pain target in humans because loss-of-function mutations cause congenital insensitivity to pain and gain-of-function mutations cause severe pain syndromes. Consequently, pharmacological inhibition has been investigated as an analgesic therapeutic strategy. ⋯ In the spared nerve injury model of neuropathic pain, ST-2530 transiently reversed mechanical allodynia. These analgesic effects were demonstrated at doses that did not affect locomotion, motor coordination, or olfaction. Collectively, results from this study indicate that pharmacological inhibition of Nav1.7 by a small molecule agent with affinity for the resting state of the channel is sufficient to produce analgesia in a range of preclinical pain models.
-
Thalamic neuroinflammation as a reproducible and discriminating signature for chronic low back pain.
Using positron emission tomography, we recently demonstrated elevated brain levels of the 18 kDa translocator protein (TSPO), a glial activation marker, in chronic low back pain (cLBP) patients, compared to healthy controls (HCs). Here, we first sought to replicate the original findings in an independent cohort (15 cLBP, 37.8 ± 12.5 y/o; 18 HC, 48.2 ± 12.8 y/o). We then trained random forest machine learning algorithms based on TSPO imaging features combining discovery and replication cohorts (totaling 25 cLBP, 42.4 ± 13.2 y/o; 27 HC, 48.9 ± 12.6 y/o), to explore whether image features other than the mean contain meaningful information that might contribute to the discrimination of cLBP patients and HC. ⋯ The random forest-based analyses revealed that although the mean is a discriminating feature, other features demonstrate similar level of importance, including the maximum, kurtosis, and entropy. Our observations suggest that thalamic neuroinflammatory signal is a reproducible and discriminating feature for cLBP, further supporting a role for glial activation in human cLBP, and the exploration of neuroinflammation as a therapeutic target for chronic pain. This work further shows that TSPO signal contains a richness of information that the simple mean might fail to capture completely.