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Peripheral joint injections are a common interventional treatment of peripheral joint-mediated pain, including arthritis, tendinopathy, and bursitis that are not responsive to conservative management. Degenerative changes of articular joints are often related to these symptoms through chronic inflammatory changes, which typically arise due to repetitive trauma, autoimmune disease, or metabolic abnormalities. The primary diagnosis for degenerative disease in the peripheral joints is osteoarthritis but can also include rheumatoid arthritis, gout, and other less common etiologies. Chronic inflammatory damage to the articular surfaces and joint capsules can lead to pain and functional decline. As such, the use of peripheral joint injections after the failure of typical conservative treatment, including physical therapy and oral medications, is common. Although these injections are typically not curative in nature, their primary objective is to decrease pain to allow functional improvement concurrently with physical and pharmaceutical modalities. Common injectates used for peripheral joint injections include local anesthetic, corticosteroid, hyaluronic acid, platelet-rich plasma, and mesenchymal stromal cells.
Learn More >Cancer pain prevalence remains high with more than 60% of patients with advanced cancer experiencing cancer-related pain. The undertreatment of pain due to concerns of opioid dependence or diversion, as well as the potential effect of opioids on tumor neogenesis, add to the suffering among cancer populations.
Learn More >Complex regional pain syndrome (CRPS) is a debilitating chronic pain disorder with no effective treatments. Growing evidence implicates aberrant immune regulation in the skin and T cell dysfunction in CRPS pathology. MicroRNA (miRNA) show promise in identifying biomarkers and disease mechanisms. miRNA cluster miR-106b-25 is dysregulated in CRPS patient whole blood and serum derived small extracellular vesicles (sEVs) compared to healthy controls. miR-106b-25 members are predicted to target several immune genes related to T cell function including CD69. We hypothesize that miR-106b-25 cluster plays a role in T-cell dysfunction by regulating members of CD69 signaling pathway. Here we examine miR-106b-25 mediated signaling in sEVs, whole blood, and skin from the tibia fracture model (TFM) of CRPS.
Learn More >The astroglial glutamate transporter-1 (GLT-1) in the hippocampus and anterior cingulate cortex (ACC) is critically involved in acute and chronic nociceptive pain. We have previously shown that 3-[[(2-Methylphenyl) methyl] thio]-6-(2-pyridinyl)-pyridazine (LDN-212320), a GLT-1 activator, in the hippocampus attenuates acute and chronic nociceptive pain. The cellular and molecular mechanisms of GLT-1 modulation in the hippocampus and ACC in chronic pain-induced cognitive deficits and anxiety-like behaviors are unknown. Here, we have examined the effects of LDN-212320 in complete Freund's adjuvant (CFA)-induced cognitive deficits and anxiety-like behaviors in mice. Furthermore, we have measured CFA-induced impaired spatial, working, and recognition memory using Y-maze and object-place recognition test. In addition, we have determined chronic pain-induced anxiety-like behaviors using elevated plus maze and marble burying test. We have also evaluated the effects of LDN-212320 on cAMP response element-binding protein (pCREB) expression in the hippocampus and ACC during CFA-induced cognitive deficits and anxiety-like behaviors using Western blot analysis and immunofluorescence assay. Pretreatment of LDN-212320 (20 mg/kg) significantly attenuated CFA-induced impaired spatial, working, and recognition memory. The LDN-212320 (20 mg/kg) significantly reduced CFA-induced anxiety-like behaviors. Additionally, LDN-212320 (20 mg/kg) significantly reversed CFA-induced decreased-pCREB expression in the hippocampus and ACC. Overall, these results suggest that the LDN-212320 prevents CFA-induced impaired cognitive behaviors and neuronal deficits via GLT-1 modulation in the hippocampus and ACC. Therefore, LDN-212320 may have therapeutic utility for the prevention and treatment of chronic pain-associated with cognitive impairments and anxiety-like behaviors.
Learn More >The development of physical dependence and addiction disorders due to misuse of opioid analgesics is a major concern with pain therapeutics. In this study, we developed a mouse model of oxycodone misuse in order to gain insight into genes and molecular pathways in reward-related brain regions that are affected by prolonged exposure to oxycodone and subsequent withdrawal in the presence or absence of chronic neuropathic pain. RNA-sequencing (RNA-seq) and bioinformatic analyses revealed that oxycodone withdrawal alone triggers robust gene expression adaptations in the nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and ventral tegmental area (VTA), with numerous genes and pathways selectively affected by oxycodone withdrawal under peripheral nerve injury states. Our pathway analysis predicted that histone deacetylase 1 (HDAC1), an epigenetic modifier with a prominent role in striatal plasticity, is a top upstream regulator in opioid withdrawal in both the NAc and mPFC. Indeed, treatment with the novel HDAC1/2 inhibitor RCY1305 attenuated behavioral manifestations of oxycodone withdrawal, with the drug being more efficacious under states of neuropathic pain. Our studies also suggest that RCY1305 treated mice did not develop conditional place preference. Since RCY1305 displays antiallodynic actions with no rewarding effects in models of neuropathic pain, inhibition of HDAC1/2 may provide an avenue for chronic pain patients dependent on opioids to transition to non-opioid analgesics. Overall, our study highlights transcriptomic events in components of the reward circuitry associated with oxycodone withdrawal under pain-naïve and prolonged neuropathic pain states, thereby providing information on possible new targets for the treatment of physical dependence to opioids and transitioning individuals to non-opioid medications for chronic pain management.
Learn More >Pain-related fear and -avoidance crucially contribute to pain chronification. People with chronic pain may adopt costly avoidance strategies above and beyond what is necessary, aligning with experimental findings of excessive fear generalization to safe movements in these populations. Furthermore, recent evidence suggests that, when avoidance is costly, it can dissociate from fear. Here, we investigated whether concurrently measured pain-related fear and costly avoidance generalization correspond in one task. We also explored whether healthy participants avoid excessively despite associated costs, and if avoidance would decrease as a function of dissimilarity from a pain-associated movement. In a robotic arm-reaching task, participants could avoid a low-cost, pain-associated movement trajectory (T+), by choosing a high-cost non-painful movement trajectory (T-), at opposite ends of a movement plane. Subsequently, in the absence of pain, we introduced three movement trajectories (G1-3) between T+ and T-, and one movement trajectory on the side of T- opposite to T+ (G4), linearly increasing in costs from T+ to G4. Avoidance was operationalized as maximal deviation from T+, and as trajectory choice. Fear learning was measured using self-reported pain-expectancy, pain-related fear, and startle eye-blink EMG. Self-reports generalized, both decreasing with increasing distance from T+. In contrast, all generalization trajectories were chosen equally, suggesting that avoidance-costs and previous pain balanced each other out. No effects emerged in the EMG. These results add to a growing body of literature showing that (pain-related) avoidance, especially when costly, can dissociate from fear, calling for a better understanding of the factors motivating, and mitigating, disabling avoidance.
Learn More >Multiple publications have shown the significant impact of the COVID-19 pandemic on US healthcare and increasing costs over the recent years in managing low back and neck pain as well as other musculoskeletal disorders. The COVID-19 pandemic has affected many modalities of treatments, including those related to chronic pain management, including both interventional techniques and opioids. While there have not been assessments of utilization of interventional techniques specific to the ongoing COVID-19 pandemic, previous analysis published with data from 2000 to 2018 demonstrated a decline in utilization of interventional techniques from 2009 to 2018 of 6.7%, with an annual decline of 0.8% per 100,000 fee-for-service (FFS) in the Medicare population. During that same time, the Medicare population has grown by 3% annually.
Learn More >Chronic neuropathic pain is a major health issue and an economic burden that affects large numbers of people. Patients suffering from chronic pain have a significantly lowered quality of life, and to date there are no effective treatments for neuropathic pain. The P2Y receptor (P2Y R) is a purinergic G-protein coupled receptor that binds nucleotide-sugars. P2RY14 is widely expressed in the body and is found in the immune system and nervous tissues. Few studies provide evidence that P2Y R is involved in pain conditions. In rat traumatic nerve injury-induced pain and post-surgical pain models, P2RY14 transcript levels were found to increase on the same side of the spinal cord as the nerve injury. In addition, P2Y R expression was elevated in an inflammatory pain model after a complete Freund's adjuvant injection in the rat trigeminal ganglia. Taken together, we hypothesize that the P2Y R plays a role in the development and maintenance of neuropathic pain. To test this, we used peripheral nerve injury model of neuropathic pain and tested several novel P2R R antagonists, which had varying potencies and bioavailabilities. Adult male ICR mice went through unilateral chronic constriction of the sciatic nerve, and on day 7 post injury they received a P2Y R antagonist intraperitoneally and the mechanical sensitivity in the hind paws was assessed. The antagonists rapidly (≤30 min) attenuated, some even reversed, mechanical sensitivity in the mice, with maximal effects observed typically within 1 h post-injection, in a dose-dependent manner. Overall, our findings provide evidence that the P2Y R is a potential therapeutic target for treating chronic pain, and its antagonists can be candidate drugs for pain treatment.
Learn More >Cannabinoids have been increasingly used to alleviate chronic pain; however, tolerance to the antinociceptive effects of cannabinoids, including delta-9-tetrahydrocannabinol (Δ -THC), may limit their therapeutic utility. Likewise, with more women than men now using medical cannabis for pain relief, it is imperative that we understand how sex may influence cannabinoid-mediated antinociception and subsequent tolerance. While studies in rats have consistently found female rats to be more sensitive to the acute antinociceptive effects of cannabinoids compared to male rats, work in our lab consistently finds the opposite finding that male mice are more sensitive to the acute antinociceptive effects of both Δ -THC and CP55,940 compared to female littermates. Studies in our lab have consistently utilized mice on a C57BL6/J (B6) background. Therefore, the purpose of the present study is to examine whether our observed sex-differences in Δ -THC-induced antinociception and tolerance are consistent across multiple mouse strains or are strain-dependent. Male and female B6 and DBA mice were first assessed for differences in acute Δ -THC-induced antinociception using the tail-flick assay across a range of doses of (0-100 mg/kg). After a significant washout period, these mice were subsequently assessed for sex-differences in antinociceptive tolerance development to 30 mg/kg Δ -THC following once-daily treatment for seven consecutive days. Consistent with our previous findings, male B6 mice were more sensitive to the acute antinociceptive effects of Δ -THC than female B6 mice. Male and female DBA, however, mice did not differ in their antinociceptive response to Δ -THC, suggesting that sex-differences in cannabinoid-induced antinociception in mice is likely strain-specific. These studies highlight the therapeutic potential of Δ -THC in pain management and underscore the importance of considering sex when evaluating their clinical utility.
Learn More >Recent evidence implicates the gut microbiome in peripheral hypersensitivity in chronic opioid use models, and in chemotherapeutic-induced hypersensitivity in mice. An important constituent of the commensal microbiome are bacterial species that ferment fibers through complex enzymatic pathways and produce short chain fatty acids, acetate, propionate, and butyrate. Butyrate is known to improve the integrity of the epithelium and enhance antimicrobial peptides thus preventing colonization by pathogenic bacteria, as well as having an established role in reducing inflammation through the inhibition of histone deacetylase. Based on this, we hypothesized that sodium butyrate can relieve peripheral hypersensitivity as well as reduce primary nociceptor hyperexcitability in experimental models of peripheral hypersensitivity. We used both paclitaxel (PAC) and morphine (MOR) animal models, which were organized into the following treatment groups: PAC (8mg/kg i.p q.d, total 4 injections) ± Sodium Butyrate (10mg/kg i.p b.i.d), MOR (escalating from 20mg/kg i.p b.i.d on day 1 to 80mg/kg i.p b.i.d on day 4) ± Sodium Butyrate (10mg/kg i.p b.i.d). PAC animals were assessed for peripheral cold hypersensitivity using an acetone evaporation assay. MOR-treated animals were assayed using a hot-plate test for opioid-induced hyperalgesia. Primary nociceptors from L4-S1 dorsal root ganglia were collected from these mice for whole-cell patch clamp electrophysiological recordings to assess for enhanced excitability. PAC-treated mice developed significant cold hypersensitivity 7 days post PAC, when compared with vehicle (average time engaging stimulated paw 2.0s vs 8.6s respectively). Butyrate ameliorated this paclitaxel-induced hypersensitivity (average time reduced to 2.5s). Similarly, MOR induced thermal hypersensitivity (Hot-plate latency of 14.8s vs 28.16s saline), which was also reversed by sodium butyrate (Hot-plate latency of 24.84s). Whole-cell patch clamp recordings revealed that PAC and MOR-treated neurons fired a greater number of regenerating action potentials compared to respective controls (PAC: 4 vs 2; MOR: 3.8 vs 2.1), indicating enhanced excitability. In-vivo butyrate treatment attenuated this enhanced excitability. Hysteresis plots of hyperexcitable cells revealed a depolarizing shift in the membrane potential of regenerating action potentials. Sodium butyrate treatment recovered this shift in membrane potential within the repetitive action potentials. Therefore, similar to the in-vivo peripheral hypersensitivity, butyrate reversed enhanced excitability of PAC and MOR-treated DRG neurons. These findings demonstrate that the short chain fatty acid, butyrate, a major metabolite of the gut microbiome plays an important role in preventing the development of drug-induced peripheral hypersensitivity.
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