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People with sensory overresponsiveness (SOR) perceive nonpainful stimuli as noxious and demonstrate hyperalgesia and lingering sensation to laboratory pain stimuli. Electroencephalography (EEG) of cortical activity at rest is widely used to explore endophenotypes but has not yet been tested in people with SOR. Therefore, we investigated the characteristics of resting-state EEG in participants with SOR.
Transient receptor potential melastatin member 8 (TRPM8) is a Ca-permeable cation channel that serves as the primary cold and menthol sensor in humans. Activation of TRPM8 by cooling compounds relies on allosteric actions of agonist and membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP), but lack of structural information has thus far precluded a mechanistic understanding of ligand and lipid sensing by TRPM8. Using cryo-electron microscopy, we determined the structures of TRPM8 in complex with the synthetic cooling compound icilin, PIP, and Ca and in complex with the menthol analog WS-12 and PIP Our structures reveal the binding sites for cooling agonists and PIP in TRPM8. Notably, PIP binds to TRPM8 in two different modes, which illustrate the mechanism of allosteric coupling between PIP and agonists. This study provides a platform for understanding the molecular mechanism of TRPM8 activation by cooling agents.
Opioid analgesics are powerful pain relievers; however, over time, pain control diminishes as analgesic tolerance develops. The molecular mechanisms initiating tolerance have remained unresolved to date. We have previously shown that desensitization of the μ-opioid receptor and interaction with β-arrestins is controlled by carboxyl-terminal phosphorylation. Here we created knockin mice with a series of serine- and threonine-to-alanine mutations that render the receptor increasingly unable to recruit β-arrestins. Desensitization is inhibited in locus coeruleus neurons of mutant mice. Opioid-induced analgesia is strongly enhanced and analgesic tolerance is greatly diminished. Surprisingly, respiratory depression, constipation, and opioid withdrawal signs are unchanged or exacerbated, indicating that β-arrestin recruitment does not contribute to the severity of opioid side effects and, hence, predicting that G-protein-biased µ-agonists are still likely to elicit severe adverse effects. In conclusion, our findings identify carboxyl-terminal multisite phosphorylation as key step that drives acute μ-opioid receptor desensitization and long-term tolerance.
Chronic pain in adults with sickle cell disease (SCD) may be the result of altered processing in the central nervous system as indicated by quantitative sensory testing (QST). Sensory pain quality descriptors on the McGill Pain Questionnaire (MPQ) are indicators of typical or altered pain mechanisms but have not been validated with QST-derived classifications.
Chronic itch is a debilitating condition characterised by excessive scratching and is a symptom frequently reported in skin diseases such as atopic dermatitis. It has been proposed that release of the cysteine protease Cathepsin S (CatS) from skin keratinocytes or immune cells resident in or infiltrating the skin could act as a pruritogen in chronic itch conditions. CatS is known to activate protease-activated receptor 2 (PAR2). We therefore hypothesised that enzymatic activation of neuronally expressed PAR2 by CatS was responsible for activation of sensory neurons and transmission of itch signals. Intradermally-injected human recombinant (hr)-CatS or the PAR2 agonist, SLIGRL-NH behaved as pruritogens by causing scratching behaviour in mice. Hr-CatS-induced scratching behaviour was prevented by CatS inhibitors and PAR2 antagonists and reduced by 50% in TRPV1 mice compared with wild-type mice, whilst no significant reduction in scratching behaviour was observed in TRPA1 mice. Cultured dorsal root ganglion (DRG) cells showed an increase in [Ca] following incubation with hr-CatS, and the percentage of neurons that responded to hr-CatS decreased in the presence of a PAR2 antagonist or in cultures of neurons from TRPV1 mice. Taken together, our results indicate CatS acts as a pruritogen via PAR2 activation in TRPV1-expressing sensory neurons.
Chronic low back pain (CLBP) is a major cause of global disability and improving management is essential. Acceptance and Commitment Therapy (ACT) is a promising treatment for chronic pain but has not been modified for physical therapy. This randomized controlled trial (RCT) compared physical therapy informed by Acceptance and Commitment Therapy (PACT) against standard care physical therapy for patients with CLBP. Patients with CLBP (duration ≥12 weeks, mean 3 years) were recruited from physical therapy clinics in four UK public hospitals. The Roland-Morris Disability Questionnaire (RMDQ) at 3 months' post randomization was the primary outcome. 248 participants (59% female, mean age=48) were recruited and 219 (88•3%) completed measures at 3 and/or 12 months' follow-up. At 3 months, PACT participants reported better outcomes for disability (RMDQ mean difference =1•07, p=0•037, 95%CI -2•08 to -0•07, d=0•2), Patient Specific Functioning (p=0.008), SF12 physical health (p=0.032), and treatment credibility (p<0.001). At 12 months' follow-up there were no significant differences between groups. PACT was acceptable to patients and clinicians and feasible to deliver. Physical therapists incorporated psychological principles successfully and treatment was delivered with high (≥80%) fidelity. Our results may inform the management of CLBP, with potential benefits for patients, health care providers and society. PERSPECTIVE: Psychologically informed physical therapy has great potential but there are challenges in implementation. The training and support included in the PACT trial enabled the intervention to be delivered as planned. This successfully reduced disability in the short but not long term. Findings could inform physical therapists' treatment of CLBP.
We aimed to assess the safety of opioids in the management of osteoarthritis (OA) in a systematic review and meta-analysis of randomized, placebo-controlled trials.
Since the failure of specific substance P antagonists to induce analgesia, the role of tachykinins in the development of neuropathic pain states has been discounted. This conclusion was reached without studies on the role of tachykinins in normal patterns of primary afferents response and sensitization or the consequences of their absence on the modulation of primary mechano-nociceptive afferents after injury. Nociceptive afferents from animals lacking tachykinins (Tac1 knockout: KO) showed a disrupted pattern of activation to tonic suprathreshold mechanical stimulation. These nociceptors failed to encode the duration and magnitude of natural pronociceptive stimuli or to develop mechanical sensitization as consequence of this stimulation. Moreover, paw edema, hypersensitivity, and weight bearing were also reduced in Tac1 KO mice 24 hours after paw incision surgery. At this time, nociceptive afferents from these animals did not show the normal sensitization to mechanical stimulation or altered membrane electrical hyperexcitability as observed in wild type animals. These changes occurred despite a similar increase in CGRP immunoreactivity in sensory neurons in Tac1 KO and normal mice. Based on these observations we conclude that tachykinins are critical modulators of primary nociceptive afferents, with a preeminent role in the electrical control of their excitability with sustained activation or injury.
The blood-brain (BBB) and blood-nerve barriers ensure protection of the nervous system but pose a challenge for treatment of pain since it restricts passage of many therapeutic drugs. Although it is unknown which blood-neural barrier is more relevant, or whether permeabilities are the same for different barriers, we proposed that the inefficiency of thioglitazone type agonists for peroxisome proliferator-activated receptor gamma (PPARɣ) is due to their difficulty in passage through the BBB. We developed a new highly BBB penetrable PPARɣ agonist for the treatment of neuropathic pain, assuming BBB permeability is a rule of thumb to estimate the overall permeability of relevant blood-neural barriers. The peak ELB00824/ pioglitazone concentration (Cmax) in the brain was 5.4 versus 0.2 µM in blood at equivalent doses (10 mg/kg i.p.). The series of studies presented here indicate that ELB00824 may be the most potent PPARɣ agonist currently known for acute reduction of neuropathic pain in trigeminal nerve in rat and mouse models. Low dose PPARɣ agonist, ELB00824 (10 mg/kg), effectively decreased neuropathic hypersensitivity in mice and rats at both acute and chronic time points, a dose 100-fold lower than the effective dose (1000 mg/kg, i.p.) of pioglitazone. Comparisons of ELB00824 alone or in combination with gabapentin or carbamazepine are provided. While PPARɣ agonists used to treat Type 2 diabetes produce several adverse side effects, sub-chronic oral toxicity study provided promising results that ELB00824 does not produce any significant short-term toxicity. The study animals of either sex remained alive and healthy with no significant alteration of body weight long-term. Toxicity study results obtained were satisfactory, with no significant alterations in any serum biochemistry parameters.
Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus with obscure underlying mechanisms. The adaptor protein APPL1 is critical in mediating the insulin sensitizing and insulin signaling. In neurons, APPL1 reportedly affects synaptic plasticity, while its role in the pathogenesis of PDN is masked. Our western blotting revealed significantly decreased APPL1 expression in the dorsal horn in streptozocin (STZ)-induced rats versus the control rats, coupled with concomitant mechanical and thermal hyperalgesia. Afterwards, the determination of exact localization of APPL1 in spinal cord by immunofluorescent staining assay revealed highly expressed APPL1 in the lamina of spinal dorsal horn in control rats, with the overexpression in neurons, microglia and underexpression in astrocytes. The APPL1 expression in laminae I and II was significantly downregulated in PDN rats. Additionally, APPL1 deficiency or overexpression contributed to the increase or decrease of Map and Bassoon, respectively. The localization and immunoactivity of APPL1 and mammalian target of rapamycin (mTOR) were determined in spinal dorsal horn in PDN rats and control rats by immunohistochemistry, suggesting pronounced decrease in APPL1 expression in the superficial layer of the spinal cord in PDN rats, with p-mTOR expression markedly augmented. APPL1 knockdown by infection with lentiviral vector facilitated the activation of mTOR and abrogated mechanical withdrawal threshold (MWT) values in PDN rats. Genetically overexpressed APPL1 significantly eliminated the activation of mTOR and resulted in the augmented MWT values and thermal withdrawal latency (TWL) values. Further, the APPL1 levels affect phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), and Akt, the phosphorylation of AMPK and Akt as well as the small GTPase, Rab5 expression in PDN rats. Our results uncovered a novel mechanism by which APPL1 deficiency facilitates the mTOR activation, and thus exacerbates the hyperalgesia in STZ-induced diabetic rats, presumably via the regulation of Rab5/Akt and AMPK signaling pathway.