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Mounting evidence indicates that the neuropeptide FF (NPFF) system is involved in the side effects of opioid usage, including antinociceptive tolerance, hyperalgesia, abuse, constipation, and respiratory depression. Our group recently discovered that the multitarget opioid/NPFF receptor agonist DN-9 exhibits peripheral antinociceptive activity. To improve its metabolic stability, antinociceptive potency, and duration, in this study, we designed and synthesized a novel cyclic disulfide analogue of DN-9, OFP011, and examined its bioactivity through cyclic adenosine monophosphate (cAMP) functional assays and behavioral experiments. OFP011 exhibited multifunctional agonistic effects at the μ-opioid and the NPFF and NPFF receptors and partial agonistic effects at the δ- and κ-opioid , as determined the cAMP functional assays. Pharmacokinetic and pharmacological experiments revealed improvement in its blood-brain barrier permeability after systemic administration. In addition, subcutaneous OFP011 exhibited potent and long-lasting antinociceptive activity the central μ- and κ-opioid receptors, as observed in different physiological and pathological pain models. At the highest antinociceptive doses, subcutaneous OFP011 exhibited limited tolerance, gastrointestinal transit, motor coordination, addiction, reward, and respiration depression. Notably, OFP011 exhibited potent oral antinociceptive activities in mouse models of acute, inflammatory, and neuropathic pain. These results suggest that the multifunctional opioid/NPFF receptor agonists with improved blood-brain barrier penetration are a promising strategy for long-term treatment of moderate to severe nociceptive and pathological pain with fewer side effects.

Intervertebral disc pathology is the most common identifiable cause of chronic lower back pain (CLBP). There are limited conservative alternatives to treat discogenic axial CLBP. Back Rx is a mobile application (app) developed to treat patients with this condition, following the Back Rx exercise program, assisted by a virtual coach.

Atopic dermatitis (AD) is a relatively common inflammatory skin disease marked by eczematous lesions and pruritus often leading to significant morbidity and quality of life impairment for those affected. Recent studies have shown that patients with skin of color (SOC) carry a larger disease burden than patients of European descent. In the USA, these disparities are partly due to structural, environmental, and interpersonal racism. From a global perspective, there is a paucity of research on the burden of atopic dermatitis and other inflammatory skin diseases experienced by the record numbers of refugees, migrants, and asylum seekers around the world. Although it is still unclear whether the true prevalence of AD in displaced communities is higher compared with the general population, those who are displaced suffer from unique risk factors that render them especially vulnerable. In this review, we outline a number of factors contributing to AD susceptibility and/or aggravation in displaced communities. These include poor living conditions, climate change events, psychological stress, and lack of access to medical care and health-related behaviors.

Patients with peripheral nerve injury, viral infection or metabolic disorder often suffer neuropathic pain due to inadequate pharmacological options for relief. Developing novel therapies has been challenged by incomplete mechanistic understanding of the cellular microenvironment in sensory nerve that trigger the emergence and persistence of pain. In this study, we report a high resolution transcriptomics map of the cellular heterogeneity of naïve and injured rat sensory nerve covering more than 110,000 individual cells. Annotation reveals distinguishing molecular features of multiple major cell types totaling 45 different subtypes in naïve nerve and an additional 23 subtypes emerging after injury. Ligand-receptor analysis revealed a myriad of potential targets for pharmacological intervention. This work forms a comprehensive resource and unprecedented window into the cellular milieu underlying neuropathic pain and demonstrates that nerve injury is a dynamic process orchestrated by multiple cell types in both the endoneurial and epineurial nerve compartments.

Continuous wound infusion with local anesthesia is an effective method for reducing postoperative pain after laparoscopic colorectal surgery. However, most subcutaneous local anesthesia is delivered through continuous injection, which can be inconvenient for patients. This study compared the effectiveness of postoperative pain relief from the application of a local poloxamer 407-based ropivacaine hydrogel (Gel) to the incision site with continuous infusion-type ropivacaine administration (On-Q) in patients undergoing laparoscopic colorectal surgery. This prospective, randomized, non-inferiority study included 61 patients who underwent laparoscopic colorectal surgery with an incision length of 3-6 cm. All 61 patients were randomly assigned to the Gel group (poloxamer 407-based 0.75% ropivacaine, 22.5 mg) or the On-Q group (0.2% ropivacaine, 4 mg/hour for two days). Postoperative analgesia was induced in all patients with intravenous patient-controlled analgesia (IV-PCA). The outcome measures, which were assessed for 72 h after surgery, included the total amount of fentanyl consumed via IV-PCA (primary endpoint), and the amount of rescue analgesia (pethidine) and postoperative pain intensity assessed using a numeric rating scale (NRS) [secondary endpoints]. The Gel was administered to 31 patients and On-Q was used for 30 patients. There was no significant difference in the total usage of fentanyl between the two groups (Gel group, 1623.98 mcg; On-Q group, 1595.12 mcg; P = 0.806). There was also no significant difference in the frequency of analgesic rescue medication use (P = 0.213) or NRS scores (postoperative 6 h, P = 0.860; 24 h, P = 0.333; 48 h, P = 0.168; and 72 h, P = 0.655) between the two groups. The Gel, which continuously delivers a local anesthetic to operative sites, can thus be considered an effective device for analgesia and pain relief for midline incisions in laparoscopic colorectal surgery.

Opioids are the therapeutic agents of choice to manage moderate to severe pain in patients with advanced cancer, however the unpredictable inter-individual response to opioid therapy remains a challenge for clinicians. While studies are few, the KCNJ6 gene is a promising target for investigating genetic factors that contribute to pain and analgesia response. This is the first association study on polymorphisms in KCNJ6 and response to methadone for pain management in advanced cancer. Fifty-four adult patients with advanced cancer were recruited across two study sites in a prospective, open label, dose individualisation study. Significant associations have been previously shown for rs2070995 and opioid response in opioid substitution therapy for heroin addiction and studies in chronic pain, with mixed results seen in postoperative pain. In this study, no associations were shown for rs2070995 and methadone dose or pain score, consistent with other studies conducted in patients receiving opioids for pain in advanced cancer. There are many challenges in conducting studies in advanced cancer with significant attrition and small sample sizes, however it is hoped that the results of our study will contribute to the evidence base and allow for continued development of gene-drug dosing guidelines for clinicians.

Pain intensity remains a primary focus clinically for sickle cell disease pain assessment despite the fact that pain quality and pain location and distribution are critical for clinical diagnosis and treatment of its etiology. However, in part because of measurement issues, scant evidence is available about pain location or its relationship to intensity and quality in adults with SCD.

Here we studied spinal neurotransmitter mechanisms involved in the reduction of mechanical hypersensitivity by inhibition of the amygdaloid central nucleus (CeA) in male and female rats with spared nerve injury (SNI) model of neuropathy. SNI induced mechanical hypersensitivity that was stronger in females. Reversible blocking of the CeA with muscimol (GABA receptor agonist) induced a reduction of mechanical hypersensitivity that did not differ between males and females. Following spinal co-administration of atipamezole (α-adrenoceptor antagonist), the reduction of mechanical hypersensitivity by CeA muscimol was attenuated more in males than females. In contrast, following spinal co-administration of raclopride (dopamine D2 receptor antagonist) the reduction of hypersensitivity by CeA muscimol was attenuated more in females than males. The reduction of mechanical hypersensitivity by CeA muscimol was equally attenuated in males and females by spinal co-administration of WAY-100635 (5-HT receptor antagonist) or bicuculline (GABA receptor antagonist). The CeA muscimol induced attenuation of ongoing pain-like behavior (conditioned place preference test) that was reversed by spinal co-administration of atipamezole in both sexes. The results support the hypothesis that CeA contributes to mechanical hypersensitivity and ongoing pain-like behavior in SNI males and females. Disinhibition of descending controls acting on spinal α-adrenoceptors, 5-HT, dopamine D2 and GABA receptors provides a plausible explanation for the reduction of mechanical hypersensitivity by CeA block in SNI. The involvement of spinal dopamine D2 receptors and α-adrenoceptors in the CeA muscimol-induced reduction of mechanical hypersensitivity is sexually dimorphic, unlike that of spinal α-adrenoceptors in the reduction of ongoing neuropathic pain.

Functionally distinct subtypes/clusters of dorsal root ganglion (DRG) neurons may play different roles in nerve regeneration and pain. However, details about their transcriptomic changes under neuropathic pain conditions remain unclear. Chronic constriction injury (CCI) of the sciatic nerve represents a well-established model of neuropathic pain, and we conducted single-cell RNA-sequencing (scRNA-seq) to characterize subtype-specific perturbations of transcriptomes in lumbar DRG neurons on day 7 post-CCI. By using mice that selectively express an enhanced in DRG neurons, we established a highly efficient purification process to enrich neurons for scRNA-seq. We observed the emergence of four prominent CCI-induced clusters and a loss of marker genes in injured neurons. Importantly, a portion of injured neurons from several clusters were spared from injury-induced identity loss, suggesting subtype-specific transcriptomic changes in injured neurons. Moreover, uninjured neurons, which are necessary for mediating the evoked pain, also demonstrated cell-type-specific transcriptomic perturbations in these clusters, but not in others. Notably, male and female mice showed differential transcriptomic changes in multiple neuronal clusters after CCI, suggesting transcriptomic sexual dimorphism in DRG neurons after nerve injury. Using as a proof-of-principle, RNAscope study provided further evidence of increased in injured neurons after CCI, supporting scRNA-seq analysis, and calcium imaging study unraveled a functional role of in neuronal excitability. These findings may contribute to the identification of new target genes and the development of DRG neuron cell-type-specific therapies for optimizing neuropathic pain treatment and nerve regeneration.

No population-based epidemiological studies have estimated pain prevalence and its characteristics in Peru. A representative sample of adults aged over 18 years (n = 502) living in metropolitan Lima, Peru was enrolled. We analyzed prevalence data of pain in the last 3 months and other pain-related characteristics. Pain prevalence was 65.3% (95% CI: 57.7-70.4%). Chronic pain prevalence was 38.5% (95% CI: 33.5-44.0%) and acute pain prevalence was 24.8% (95% CI: 20.7-29.0%). In participants with chronic pain, almost half (55.7%) reported having not used any medication. Pain is prevalent in this population and our results suggest high undertreatment rates.