Pain
-
Biological differences in sensory processing between human and model organisms may present significant obstacles to translational approaches in treating chronic pain. To better understand the physiology of human sensory neurons, we performed whole-cell patch-clamp recordings from 141 human dorsal root ganglion (hDRG) neurons from 5 young adult donors without chronic pain. Nearly all small-diameter hDRG neurons (<50 μm) displayed an inflection on the descending slope of the action potential, a defining feature of rodent nociceptive neurons. ⋯ Compared to electrically evoked action potentials, chemically induced action potentials were triggered from less depolarized thresholds and showed distinct afterhyperpolarization kinetics. These data indicate that most small/medium hDRG neurons can be classified as nociceptors, that they respond directly to compounds that produce pain and itch, and that they can be activated and sensitized by inflammatory mediators. The use of hDRG neurons as preclinical vehicles for target validation is discussed.
-
Candidate gene studies have revealed limited genetic bases for opioid analgesic response variability. Genome-wide association studies facilitate impartial queries of common genetic variants, allowing identification of novel genetic contributions to drug effect. Illumina (Illumina Inc, San Diego, CA, USA) single nucleotide polymorphism (SNP) arrays were used to investigate SNP associations with total morphine requirement as a quantitative trait locus and with postoperative pain in a retrospective population of opioid-naïve children ages 4-18years who had undergone day surgery tonsillectomy and adenoidectomy. ⋯ No association with morphine dose was detected in African Americans (AA) (n=241). Postoperative pain scores ≥ 7/10 were associated with rs795484 (G>A) in the EC cohort (odds ratio 2.35, 95% CI 1.56-3.52, P<0.00005) and this association replicated in AA children (odds ratio 1.76, 95% CI 1.14-2.71, P<0.01). Variants in TAOK3 encoding the serine/threonine-protein kinase, TAO3, are associated with increased morphine requirement in children of EC ancestry and with increased acute postoperative pain in both EC and AA subjects.
-
Chronic neuropathic pain causes abnormal sensitivities such as hyperalgesia and allodynia, and emotional abnormalities such as anxiety and depression. Although spinal cord microglia are involved in abnormal sensitivity to neuropathic pain, no previous studies have examined the mechanism of neuropathic pain-induced anxiety. Here, we examined the involvement of bone marrow (BM)-derived microglia aggregated in the amygdalae of mice with chronic neuropathic pain in the development of anxiety-like behavior. ⋯ Oral administration of a CCR2 antagonist decreased the number of BM-derived microglia in the CeA, and successfully reversed the anxiety-like behavior and hypersensitivity to mechanical stimuli in PSNL-treated mice. Microinjections of an IL-1β receptor antagonist directly into the CeA successfully reversed the anxiety-like behavior in the PSNL-treated mice even though the neuropathic pain persisted. These results suggest that the recruitment of BM-derived microglia to the CeA via the MCP-1/CCR2 axis and neuron-microglia interactions might be important in the pathogenesis of neuropathic pain-induced anxiety.
-
The effective management of pain is a longstanding public health concern. Morphine-like opioids have long been front-line analgesics, but produce undesirable side effects that can limit their application. Slow progress in the introduction of novel improved medications for pain management over the last 5 decades has prompted a call for innovative translational research, including new preclinical assays. ⋯ Next, sessions were conducted in which the temperature of the thermode was increased stepwise until responding stopped, permitting the determination of stable nociceptive thresholds. Tests revealed that several opioid analgesics, but not d-amphetamine or Δ(9)-THC, produced dose-related increases in threshold that were antagonist sensitive and efficacy dependent, consistent with their effects using traditional measures of antinociception. Unlike traditional reflex-based measures, however, the results also permitted the concurrent evaluation of response disruption, providing an index with which to characterize the behavioral selectivity of antinociceptive drugs.
-
Extracellular high mobility group box-1 protein (HMGB1) plays important roles in the pathogenesis of nerve injury- and cancer-induced pain. However, the involvement of spinal HMGB1 in arthritis-induced pain has not been examined previously and is the focus of this study. Immunohistochemistry showed that HMGB1 is expressed in neurons and glial cells in the spinal cord. ⋯ Furthermore, the pro-nociceptive effect of i.t. injection of HMGB1 persisted in Tlr2- and Rage-, but was absent in Tlr4-deficient mice. The same pattern was observed for HMGB1-induced spinal microglia and astrocyte activation and cytokine induction. These results demonstrate that spinal HMGB1 contributes to nociceptive signal transmission via activation of TLR4 and point to disulfide HMGB1 inhibition as a potential therapeutic strategy in treatment of chronic inflammatory pain.