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SP16 is an innovative peptide derived from the carboxyl-terminus of α1-Antitrypsin (AAT), corresponding to residues 364-380, and contains recognition sequences for the low-density lipoprotein receptor-related protein-1 (LRP1). LRP1 is an endocytic and cell-signaling receptor that regulates inflammation. Deletion of Lrp1 in Schwann cells increases neuropathic pain; however, the role of LRP1 activation in nociceptive and neuropathic pain regulation remains unknown. Herein, we show that SP16 is bioactive in sensory neurons in vitro. Neurite length and regenerative gene expression were increased by SP16. In PC12 cells, SP16 activated Akt and ERK1/2 cell-signaling in an LRP1-dependent manner. When formalin was injected into mouse hind paws, to model inflammatory pain, SP16 dose-dependently attenuated nociceptive pain behaviors in the early and late phases. In a second model of acute pain using capsaicin, SP16 significantly reduced paw licking in both male and female mice (p < .01) similarly to enzymatically inactive tissue plasminogen activator, a known LRP1 interactor. SP16 also prevented development of tactile allodynia after partial nerve ligation and this response was sustained for nine days (p < .01). Immunoblot analysis of the injured nerve revealed decreased CD11b (p < .01) and Toll-like receptor-4 (p < .005). In injured dorsal root ganglia SP16 reduced CD11b cells (p < .05) and GFAP (p < .005), indicating that inflammatory cell recruitment and satellite cell activation were inhibited. In conclusion, administration of SP16 blocked pain-related responses in three distinct pain models, suggesting efficacy against acute nociceptive, inflammatory, and neuropathic pain. SP16 also attenuated innate immunity in the PNS. These studies identify SP16 as a potentially effective treatment for pain.
Learn More >The rewarding effect of opiates is mediated through dissociable neural systems in drug naïve and drug-dependent states. Neuroadaptations associated with chronic drug use are similar to those produced by chronic pain, suggesting that opiate reward could also involve distinct mechanisms in chronic pain and pain-naïve states. We tested this hypothesis by examining the effect of dopamine (DA) antagonism on morphine reward in a rat model of neuropathic pain.Neuropathic pain was induced in male Sprague-Dawley rats through chronic constriction (CCI) of the sciatic nerve; reward was assessed in the conditioned place preference (CPP) paradigm in separate groups at early (4-8 days post-surgery) and late (11-15 days post-surgery) phases of neuropathic pain. Minimal effective doses of morphine that produced a CPP in early and late phases of neuropathic pain were 6 mg/kg and 2 mg/kg respectively. The DA D1 receptor antagonist, SCH23390, blocked a morphine CPP in sham, but not CCI, rats at a higher dose (0.5 mg/kg), but had no effect at a lower dose (0.1 mg/kg). The DA D2 receptor antagonist, eticlopride (0.1 and 0.5 mg/kg), had no effect on a morphine CPP in sham or CCI rats, either in early or late phases of neuropathic pain. In the CPP paradigm, morphine reward involves DA D1 mechanisms in pain-naïve but not chronic pain states. This could reflect increased sensitivity to drug effects in pain versus no pain conditions and/or differential mediation of opiate reward in these two states.
Learn More >To observe and evaluate the effect of a single intravenous injection of low-dose esketamine on post-operative pain and post-partum depression (PPD) in cesarean delivery patients.
Learn More >Even as prescription opioid dispensing rates have begun to decrease, the use of illicit opioids such as heroin and fentanyl has increased. Thus, the end of the opioid epidemic is not in sight, and treating patients that are addicted to opioids remains of utmost importance. Currently, the primary pharmacotherapies used to treat opioid addiction over the long term are the opioid antagonist naltrexone, the partial-agonist buprenorphine, and the full agonist methadone. Naloxone is an antagonist used to rapidly reverse opioid overdose. While these treatments are well-established and used regularly, the gravity of the opioid epidemic necessitates that all possible avenues of treatment be explored. Therefore, in this narrative review, we analyze current literature regarding use of the alternative medications ketamine, noribogaine, and cannabinoids in treating patients suffering from opioid use disorder. Beyond its use as an anesthetic, ketamine has been shown to have many applications in several medical specialties. Of particular interest to the subject at hand, ketamine is promising in treating individuals addicted to opioids, alcohol, and cocaine. Therapeutically administered cannabinoids have been proposed for the treatment of multiple illnesses. These include, but are not limited to epilepsy, Parkinson's disease, multiple sclerosis, chronic pain conditions, anxiety disorders, and addiction. The cannabinoid dronabinol has been seen to have varying effects. High doses appear to reduce withdrawal symptoms but this comes at the expense of increased adverse side effects such as sedation and tachycardia. Noribogaine is a weak MOR antagonist and relatively potent KOR agonist, which may explain the clinical anti-addictive effects. More research should be done to assess the viability of these medications for the treatment of OUD and withdrawal.
Learn More >Osteoarthritis pain is often thought of as a pain driven by nerves that innervate the soft tissues of the joint, but there is emerging evidence for a role for nerves that innervate the underlying bone. In this mini review we cite evidence that subchondral bone lesions are associated with pain in osteoarthritis. We explore recent studies that provide evidence that sensory neurons that innervate bone are nociceptors that signal pain and can be sensitized in osteoarthritis. Finally, we describe neuronal remodeling of sensory and sympathetic nerves in bone and discuss how these processes can contribute to osteoarthritis pain.
Learn More >Previous research supports the usefulness of hypnosis (HYP), mindfulness meditation (MM), and prayer as pain self-management strategies in adults with chronic pain. However, their effects on acute pain have been less researched, and no previous head-to-head study compared the immediate effects of these three approaches on pain-related outcomes. This study compared the immediate effects of HYP, MM, and Christian prayer (CP) on pain intensity, pain tolerance, and stress as assessed by heart rate variability (HRV).
Learn More >Knee osteoarthritis (KOA) is a painful chronic disorder. Evidence has shown that a history of chronic pain plays an important role in shaping empathy. Empathy, a valuable indicator of social functioning that refers to an individual's ability to share the experiences of others, however, has been overlooked in KOA patients. This study aimed to investigate empathy and its association with clinical pain in KOA patients.
Learn More >Chronic, abdominal pain remains a problem in a subset of patients after cholecystectomy. The cause is often obscure but central sensitization may be an important component and could theoretically be mediated by spinal PGE2, which is regulated by several cytokines. The aim of the study was to examine cerebrospinal fluid (CSF) of participants with post cholecystectomy syndrome and healthy volunteers for signs of PGE2 and cytokine mediated central sensitization.
Learn More >Persistent expression of NLRP3 in spinal microglia promotes development of lumbar disc degeneration.
Activated microglia play a critical role in the development of lumbar disc degeneration (LDD), which is a severe disease that causes neuropathic pain in affected people. Interleukin 1β (IL-1β) is a proinflammatory cytokine produced and secreted by activated microglia to induce the inflammation and the subsequent degradation of the disease discs. Recent findings suggest that activation of IL-1β in cells usually requires the involvement of NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-induced formation of inflammasome. However, the importance of NLRP3 in spinal microglia in LDD is not known and thus addressed in the current study.
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