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Postherpetic itch (PHI), or herpes zoster itch, is an intractable and poorly understood disease. We targeted 94 herpes zoster patients to investigate their pain and itch intensities at three separate stages of the condition (acute, subacute, and chronic). We used painDETECT questionnaire (PDQ) scores to investigate the correlation between PHI and neuropathic pain. Seventy-six patients were able to complete follow-up surveys. The prevalence of PHI was 47/76 (62%), 28/76 (37%), and 34/76 (45%) at the acute, subacute, and chronic stages, respectively. PHI manifestation times and patterns varied. We investigated the relationship of PHI with neuropathic pain using the visual analog scale (VAS), which is a measure of pain intensity, and the PDQ, which is a questionnaire used to evaluate the elements of neuropathic pain. The VAS and PDQ scores did not differ significantly between PHI-positive and PHI-negative patients. A large neuropathic component was not found for herpes zoster itch, suggesting that neuropathic pain treatments may not able to adequately control the itch. Accordingly, we suggest that a more PHI-focused therapy is required to address this condition.
Although the evidence of the attentional bias of chronic pain individuals toward pain-related information is established in the literature, few studies examined the time course of attention toward pain stimuli and the role of pain catastrophizing on attentional engagement toward pain-related information. This study examined the time course of attention to pain-related information and the role of pain catastrophizing on attentional engagement for pain-related information. Participants were fifty young adult participants with chronic pain (35% male, 65% female; M = 21.8 years) who completed self-report questionnaires assessing pain catastrophizing levels (Pain Catastrophizing Scale (PCS)), depression (the Center for Epidemiologic Studies Depression Scale (CES-D)), anxiety (State-Trait Anxiety Inventory (STAI)), and pain disability (the Pain Disability Index: (PDI)). Attentional engagements to pain- and anger-related information were measured by the eye tracker. Significant interaction effects were found between (1) time and stimulus type for pain-related information ( (5, 245) = 11.55, < 0.001) and (2) bias scores and pain catastrophizing ( (1, 48) = 6.736, < 0.05). These results indicated that the degree of increase for pain bias scores were significantly greater than anger bias scores as levels of pain catastrophizing increased. Results of the present study provided the evidence for the attentional bias and information processing model which has clinical implications; high levels of pain catastrophizing may impair individuals' ability to cope with chronic pain by increasing attentional engagement toward pain-related information. The present study can add knowledge to attentional bias and pain research as this study investigated the time course of attention and the role of pain catastrophizing on attentional engagement toward pain-related information for adults with chronic pain conditions.
Pain is the most severe and common symptom of endometriosis. Its underlying pathogenetic mechanism is poorly understood. Nerve sensitization is a particular research challenge, due to the limitations of general endometriosis models and sampling nerve tissue from patients. The chemokine fractalkine (FKN) has been demonstrated to play a key role in various forms of neuropathic pain, while its role in endometriotic pain is unknown. Our study was designed to explore the function of FKN in the development and maintenance of peripheral hyperalgesia and central sensitization in endometriosis using a novel endometriosis animal model developed in our laboratory. After modeling, behavioral tests were carried out and the optimal time for molecular changes was obtained. We extracted ectopic tissues and L4-6 spinal cords to detect peripheral and central roles for FKN, respectively. To assess morphologic characteristics of endometriosis-like lesions-as well as expression and location of FKN/CX3CR1-we performed H&E staining, immunostaining, and western blotting analyses. Furthermore, inhibition of FKN expression in the spinal cord was achieved by intrathecal administration of an FKN-neutralizing antibody to demonstrate its function. Our results showed that implanted autologous uterine tissue around the sciatic nerve induced endometriosis-like lesions and produced mechanical hyperalgesia and allodynia. FKN was highly expressed on macrophages, whereas its receptor CX3CR1 was overexpressed in the myelin sheath of sciatic nerve fibers. Overexpressed FKN was also observed in neurons. CX3CR1/pp38-MAPK was upregulated in activated microglia in the spinal dorsal horn. Intrathecal administration of FKN-neutralizing antibody not only reversed the established mechanical hyperalgesia and allodynia, but also inhibited the expression of CX3CR1/pp38-MAPK in activated microglia, which was essential for the persistence of central sensitization. We concluded that the FKN/CX3CR1 signaling pathway might be one of the mechanisms of peripheral hyperalgesia in endometriosis, which requires further studies. Spinal FKN is important for the development and maintenance of central sensitization in endometriosis, and it may further serve as a novel therapeutic target to relieve persistent pain associated with endometriosis.
Hysteroscopy is increasingly performed in an outpatient setting. Pain is the primary reason for abandonment of procedure or incomplete assessment. There is no consensus upon routine use of analgesia during hysteroscopy.
The role of low-level laser therapy (LLLT) in the management of carpal tunnel syndrome (CTS) is controversial. While some trials have shown distinct advantages of LLLT over placebo and some other non-surgical treatments, other trials have not.
Sublethal injury triggers long-lasting sensitization of defensive responses in most species examined, suggesting the involvement of powerful evolutionary selection pressures [1]. In humans, this persistent nociceptive sensitization is often accompanied by heightened sensations of pain and anxiety [2]. While experimental [3] and clinical [4] evidence support the adaptive value of immediate nociception during injury, no direct evidence exists for adaptive benefits of long-lasting sensitization after injury. Recently, we showed that minor injury produces long-term sensitization of behavioral and neuronal responses in squid, Doryteuthis pealei [5, 6]. Here we tested the adaptive value of this sensitization during encounters between squid and a natural fish predator. Locomotion and other spontaneous behaviors of squid that received distal injury to a single arm (with or without transient anesthesia) showed no measurable impairment 6 hr after the injury. However, black sea bass given access to freely swimming squid oriented toward and pursued injured squid at greater distances than uninjured squid, regardless of previous anesthetic treatment. Once targeted, injured squid began defensive behavioral sequences [7, 8] earlier than uninjured squid. This effect was blocked by brief anesthetic treatment that prevented development of nociceptive sensitization [6, 9]. Importantly, the early anesthetic treatment also reduced the subsequent escape and survival of injured, but not uninjured, squid. Thus, while minor injury increases the risk of predatory attack, it also triggers a sensitized state that promotes enhanced responsiveness to threats, increasing the survival (Darwinian fitness) of injured animals during subsequent predatory encounters.
Opium is one of the world's oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled µ-opioid receptor (µ-OR) in the central nervous system. Here we describe the 2.8 Å crystal structure of the mouse µ-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the µ-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.
The expression of potassium ion channel subunit 1.2 (Kv1.2) in the dorsal root ganglion (DRG) influences the excitability of neurons, which contributes to the induction and development of neuropathic pain (NPP); however, the molecular mechanisms underlying the downregulation of Kv1.2 in NPP remain unknown. Histone deacetylase (HDAC) inhibitors are reported to attenuate the development of pain hypersensitivity in rats with NPP. Whether HDAC inhibitors contribute to regulation of Kv1.2 expression, and which specific HDAC subunit is involved in NPP, remain unexplored. In this study we established a chronic constrictive injury (CCI) model and used western blot, quantitative real-time PCR, immunostaining, intrathecal injection, and siRNA methods to explore which HDAC subunit is involved in regulating Kv1.2 expression to mediate NPP. Our results demonstrated that nerve injury led to upregulation of HDAC1 expression in the DRG, and of HDAC2 in the DRG and spinal cord. Double-labeling immunofluorescence histochemistry showed that Kv1.2 principally co-localized with HDAC2, but not HDAC1, in NF200-positive large neurons of the DRG. Intrathecal injection with the HDAC inhibitor, suberoylanilide hydroxamic acid, attenuated mechanical and thermal hypersensitivity and reversed the decreased expression of Kv1.2 in rats with CCI. Furthermore, treatment with HDAC2, but not HDAC1, siRNA also relieved mechanical and thermal hypersensitivity and upregulated the Kv1.2 expression in this model. In vitro transfection of PC12 cells with HDAC2 and HDAC1 siRNA confirmed that only HDAC2 siRNA could regulate the expression of Kv1.2. These findings suggest that HDAC2, but not HDAC1, is involved in NPP through regulation of Kv1.2 expression.
Neuropathic pain is a consequence of damage to the central nervous system (CNS), for example, cerebrovascular accident, multiple sclerosis or spinal cord injury, or peripheral nervous system (PNS), for example, painful diabetic neuropathy (PDN), postherpetic neuralgia (PHN), or surgery. Evidence suggests that people suffering from neuropathic pain are likely to seek alternative modes of pain relief such as herbal medicinal products due to adverse events brought about by current pharmacological agents used to treat neuropathic pain. This review includes studies in which participants were treated with herbal medicinal products (topically or ingested) who had experienced neuropathic pain for at least three months.
The role of urea in neuronal degeneration and sensitization: an in vitro model of uremic neuropathy.
Background Uremic neuropathy commonly affects patients with chronic kidney disease (CKD), with painful sensations in the feet, followed by numbness and weakness in the legs and hands. The symptoms usually resolve following kidney transplantation, but the mechanisms of uremic neuropathy and associated pain symptoms remain unknown. As blood urea levels are elevated in patients with CKD, we examined the morphological and functional effects of clinically observed levels of urea on sensory neurons. Methods Rat DRG neurons were treated with 10 or 50 mMol/L urea for 48 hours, fixed and immunostained for PGP9.5 and βIII tubulin immunofluorescence, ,. Neurons were also immunostained for TRPV1, TRPM8 and Gap43 expression, and the capsaicin sensitivity of urea or vehicle treated neurons was determined. Results Urea treated neurons had degenerating neurites with diminished PGP9.5 immunofluorescence, and swollen, retracted growth cones. βIII tubulinappeared clumped after urea treatment. Neurite lengths were significantly reduced to 60 ± 2.6 % (10 mMol/L, **P<0.01), and to 56.2 ± 3.3 %, (50 mMol/L, **P<0.01), urea treatment for 48 hours, compared with control neurons. Fewer neurons survived urea treatment, with 70.08 ± 13.3% remaining after10 mMol/L (*P<0.05), and 61.49 ± 7.4 % after 50 mMol/L urea treatment (**P<0.01), compared with controls. The proportion of neurons expressing TRPV1 was reduced after urea treatment, but not TRPM8 expressing neurons. In functional studies, treatment with urea resulted in dose-dependent neuronal sensitization. Capsaicin responses were significantly increased to 115.29 ± 3.4 % (10 mMol/L, **P<0.01) and 125.3 ± 4.2% (50 mMol/L, **P<0.01), compared with controls. Sensitization due to urea was eliminated in the presence of the TRPV1 inhibitor SB705498, the MEK inhibitor PD98059, the PI3 kinase inhibitor LY294002, and the TRPM8 inhibitor AMTB. Conclusion Neurite degeneration and sensitization are consistent with uremic neuropathy, , and provide a disease-relevant model to test new treatments.