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Patients with neuropathic pain often experience exaggerated pain and anxiety. Central sensitization has been linked with the maintenance of neuropathic pain and may become an autonomous pain generator. Conversely, emerging evidence accumulated that central sensitization is initiated and maintained by ongoing nociceptive primary afferent inputs. However, it remains elusive what mechanisms underlie this phenomenon and which peripheral candidate contributes to central sensitization that accounts for pain hypersensitivity and pain-related anxiety. Previous studies have implicated peripherally-localized cGMP-dependent protein kinase I (PKG-I) in plasticity of nociceptors and spinal synaptic transmission as well as inflammatory hyperalgesia. However, whether peripheral PKG-I contributes to cortical plasticity and hence maintains nerve injury-induced pain hypersensitivity and anxiety is unknown. Here we demonstrated significant upregulation of PKG-I in ipsilateral L3 DRG, no change in L4 DRG and downregulation in L5 DRG upon spared nerve injury (SNI). Genetic ablation of PKG-I specifically in nociceptors or posttreatment with intervertebral foramen injection of PKG-I antagonist, KT5823 attenuated the development and maintenance of SNI-induced bilateral pain hypersensitivity and anxiety. Mechanistic analysis revealed that activation of PKG-I in nociceptors is responsible for synaptic potentiation in ACC upon peripheral neuropathy via presynaptic mechanisms involving BDNF signaling. Our results revealed that PKG-I expressed in nociceptors is a key determinant for cingulate synaptic plasticity after nerve injury, which contributes to the maintenance of pain hypersensitivity and anxiety. Thereby, this study presents a strong basis for opening up a novel therapeutic target, PKG-I in nociceptors for treatment of comorbidity of neuropathic pain and anxiety with least side effects.
Learn More >The subgenual anterior cingulate cortex (sgACC) plays an important role in pain modulation. We previously demonstrated sex differences in sgACC functional connectivity (FC) in healthy individuals. Given that many chronic pain conditions show sex differences in prevalence, here we tested the hypothesis that people with chronic pain exhibit a sex-specific pattern of abnormal sgACC FC. We acquired resting state functional magnetic resonance imaging (fMRI) data from 156 (82W:74M) healthy participants and 38 (19W:19M) people with chronic low back pain resulting from ankylosing spondylitis (AS), a condition that predominantly affects men. We confirmed that there are sex differences in sgACC FC in our large cohort of healthy adults; women had greater sgACC FC with the precuneus, a key node of the default mode network, and men had greater sgACC FC with the posterior insula and the operculum. Next, we identified an interaction effect between sex and pain status (healthy/chronic pain) for sgACC FC. Within the chronic pain group, women had greater sgACC FC than men to the salience, default mode, and sensorimotor networks. Compared to healthy women, women with chronic pain also had greater sgACC FC to the precuneus and ACC and lower FC to the hippocampus and frontal regions. No differences in sgACC FC were seen in men with vs. without chronic pain. Our findings indicate that abnormal sgACC circuitry is unique to women but not men with AS-related chronic pain. These sex differences may impact the benefit of therapeutics that target the sgACC for chronic pain.
Learn More >Patients' pain behavior plays an important role in the interaction between patients and their partners, as acknowledged in operant models of pain. However, despite the considerable research attention to pain behaviors, the underlying motives of such behaviors are still unclear. The current study explores the motives to engage in pain behaviors, and the possible discrepancies between patients' and partners' perceptions of those motives.
Learn More >A hallmark of migraine is photophobia. In mice, photophobia-like behavior is induced by calcitonin gene-related peptide (CGRP), a neuropeptide known to be a key player in migraine. In this study, we sought to identify sites within the brain from which CGRP could induce photophobia.
Learn More >Extrasynaptic α -subunit containing GABA (α -GABA ) receptors participate in chronic pain. Previously, we reported a sex difference in the action of α -GABA receptors in dysfunctional pain. However, the underlying mechanisms remain unknown. The aim of this study was to examine this sexual dimorphism in neuropathic rodents and the mechanisms involved. Female and male Wistar rats or ICR mice were subjected to nerve injury followed by α -GABA receptor inverse agonist intrathecal administration, L-655,708. The drug produced an antiallodynic effect in nerve-injured female rats and mice, and a lower effect in males. We hypothesized that changes in α -GABA receptor, probably influenced by hormonal and epigenetic status, might underlie this sex-difference. Thus, we performed qPCR and western blot. Nerve injury increased α -GABA mRNA and protein in female dorsal root ganglia (DRG) and decreased them in DRG and spinal cord of males. To investigate the hormonal influence over α -GABA receptor actions, we performed nerve injury to ovariectomized rats and reconstituted them with 17β-estradiol (E2). Ovariectomy abrogated L-655,708 antiallodynic effect and E2 restored it. Ovariectomy decreased α -GABA receptor and ER α protein in DRG of neuropathic female rats, while E2 enhanced them. Since DNA methylation might contribute to α -GABA receptor down-regulation in males, we examined CpG island DNA methylation of α -GABA receptor coding gene through pyrosequencing. Nerve injury increased methylation in male, but not female rats. Pharmacological inhibition of DNA methyltransferases increased α -GABA receptor and enabled L-655,708 antinociceptive effect in male rats. These results suggest that α -GABA receptor is a suitable target to treat chronic pain in females.
Learn More >Introduction Fixed-dose combination analgesic regimens may be similarly effective to opioid monotherapy but with potentially less risk. A number of individualized combination regimens can be created, including nonopioid agents such as acetaminophen and nonsteroidal anti-inflammatory drugs, opioids, and adjunctive agents such as gabapentin, pregabalin, and muscle relaxants. Areas Covered When such combinations have a synergistic effect, analgesic benefits may be enhanced. Many combination analgesic regimens are opioid sparing, which sometimes but not always results in reduced opioid-associated side effects. Safety concerns for all analgesics must be considered but postoperative analgesia is typically administered for a brief period (days), reducing risks that may occur with prolonged exposure. Expert Opinion Judiciously considered combination analgesic regimens can be effective postoperative analgesics that reduce opioid consumption without compromising pain control, which are important factors for patient recovery and satisfaction. The specific combinations used must be based on the patient, the type and duration of the surgical procedure, and complementary mechanisms of action of the agents used. In opioid-sparing combination analgesic regimens, the short-term use of small doses of opioids in this setting may be helpful for appropriate patients.
Learn More >The association between migraine, depression, and anxiety has been established, but the impact of these psychiatric comorbidities on functional impairment in people with migraine has been under-investigated. The purpose of this cross-sectional observational study was to investigate the relationship between anxiety and depression symptoms on migraine-related disability, pain interference, work interference, and career success in a cohort of patients with migraine.
Learn More >Pain management in both outpatient and inpatient settings demands a multidisciplinary approach entailing medical, physical and psychological therapies. Among these, multimodal analgesic regimens stand out as a promising treatment options. Cyclo-oxygenase (COX) inhibitor/opioid receptor agonist combinations hold great potential as effective pillars in the multimodal pain management by providing adequate analgesia with fewer safety risks due to COX inhibitors' opioid-sparing effect. Thus, these combinations, either freely or in fixed-dose formulation, offer a feasible option for the prescribing clinicians who seek to maximise therapeutic effect while simultaneously minimise adverse effects. The selection of the appropriate non-steroidal anti-inflammatory drug (NSAID) and opioid agent at optimal doses is essential. It should be tailored to the patients' analgesic necessities, and his/her gastrointestinal and cardiovascular risk, and potential concurrent aspirin use. Moreover, it should allow for addiction risk and the potential opioid-induced bowel dysfunction and constipation. To ensure an optimal match between the characteristics of the patient and the properties of the chosen medication, and to guide adequate and well-tolerated treatment decisions, it is of paramount importance to expand clinicians' knowledge of the currently available COX inhibitor/opioid receptor agonist combinations. This invited narrative review deals with the literature evidence covering the components of multimodal opioid-sparing analgesic regimens. Also, it provides insights into the clinically relevant choice criteria to ensure a patient-tailored analgesia.
Learn More >To analyse the number of, timing of, and reasons for early termination of interdisciplinary pain rehabilitation (IPR).
Learn More >The ACTTION-APS-AAPM Acute Pain Taxonomy (AAAPT) project relies on the identification of modulators to improve characterization and classification of acute pain conditions. In the frame of the AAAPT effort, this paper presents an overview of common biological modulators of acute pain.
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