Richard Slivicki

• Instructor at Washington University in St. Louis

Opioid analgesics represent a critical treatment for chronic pain in the analgesic ladder of the World Health Organization. However, their use can result in a number of unwanted side-effects including incomplete efficacy, constipation, physical dependence, and overdose liability. Cannabinoids enhance the pain-relieving effects of opioids in preclin...

Background Activation of cannabinoid CB1 receptors suppresses pathological pain but also produces unwanted central side effects. We hypothesized that a positive allosteric modulator (PAM) of CB1 signaling would suppress inflammatory and neuropathic pain without producing cannabimimetic effects or physical dependence. We also asked whether a CB1-PAM...

Activation of cannabinoid receptor type 1 (CB1) produces analgesia in a variety of preclinical models of pain; however, engagement of central CB1 receptors is accompanied by unwanted side effects, such as psychoactivity, tolerance and dependence. Therefore, some efforts to develop novel analgesics have focused on targeting peripheral CB1 receptors...

Use of prescription opioids, particularly oxycodone, is an initiating factor driving the current opioid epidemic. There are several challenges with modelling oxycodone abuse. First, prescription opioids including oxycodone are orally self‐administered and have different pharmacokinetics and dynamics than morphine or fentanyl, which have been more c...

The current opioid overdose epidemic highlights the urgent need to develop safer and more effective treatments for chronic pain¹. Cannabinoid receptor type 1 (CB1) is a promising non-opioid target for pain relief, but its clinical use has been limited by centrally mediated psychoactivity and tolerance. We overcame both issues by designing periphera...

Despite the prevalence of chronic pain, the approval of novel, non-opioid therapeutics has been slow. A major translational challenge in analgesic development is the difference in gene expression and functional properties between human and rodent dorsal root ganglia (DRG) sensory neurons. Extensive work in rodents suggests that sensitization of noc...

Introduction: Autoantibodies to the Fibroblast Growth Factor Receptor 3 (FGFR3-AAbs) have been associated with idiopathic sensory-predominant neuropathy. The pathogenicity of FGFR3-AAbs in this disorder is unknown. Pathogenic mechanisms of autoantibodies in other dysimmune neuropathies commonly involve their direct binding to antigens on either neu...

In response to changes in activity induced by environmental cues, neurons in the central nervous system undergo homeostatic plasticity to sustain overall network function during abrupt changes in synaptic strengths. Homeostatic plasticity involves changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing...

Opioid overdose accounts for nearly 75,000 deaths per year in the United States, now a leading cause of mortality among young people aged 18 to 45 years. At overdose levels, opioid-induced respiratory depression becomes fatal without the administration of naloxone within minutes. Currently, overdose survival relies on bystander intervention, requir...

Opioid overdose accounts for nearly 75,000 deaths per year in the United States, representing a leading cause of mortality amongst the prime working age population (25-54 years). At overdose levels, opioid-induced respiratory depression becomes fatal without timely administration of the rescue drug naloxone. Currently, overdose survival relies enti...

Sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli to the central nervous system. Single-cell RNA sequencing has provided insights into the diversity of sensory ganglia cell types in rodents, nonhuman primates, and humans, but it remains difficult to c...

Oxycodone is commonly prescribed for moderate to severe pain disorders. While efficacious, long-term use can result in tolerance, physical dependence, and the development of opioid use disorder. Cannabis and its derivatives such as delta9-Tetrahydrocannabinol (delta9-THC) have been reported to enhance oxycodone analgesia in animal models and in hum...

Bradykinin is a peptide implicated in inflammatory pain in both humans and rodents. In rodent sensory neurons, activation of B1 and B2 bradykinin receptors induces neuronal hyperexcitability. Recent evidence suggests that human and rodent dorsal root ganglia (DRG), which contain the cell bodies of sensory neurons, differ in the expression and funct...

Peripheral sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli including touch, temperature, and pain to the central nervous system. Recent advances in single-cell RNA-sequencing (scRNA-seq) have provided new insights into the diversity of sensory gangl...

In response to changes in activity induced by environmental cues, neurons in the central nervous system undergo homeostatic plasticity to sustain overall network function during abrupt changes in synaptic strengths. Homeostatic plasticity involves changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing...

Bradykinin is a peptide implicated in inflammatory pain in both humans and rodents. In rodent sensory neurons, activation of B1 and B2 bradykinin receptors induces neuronal hyperexcitability. Recent evidence suggests that human and rodent dorsal root ganglia (DRG), which contain the cell bodies of sensory neurons, differ in the expression and funct...

The cover image is based on the Original Article Oral oxycodone self‐administration leads to features of opioid misuse in male and female mice by Richard A. Slivicki et al., https://doi.org/10.1111/adb.13253.

Neurotransmitters and neuromodulators mediate communication between neurons and other cell types; knowledge of release dynamics is critical to understanding their physiological role in normal and pathological brain function. Investigation into transient neurotransmitter dynamics has largely been hindered due to electrical and material requirements...

Use of prescription opioids, particularly oxycodone is an initiating factor driving the current opioid epidemic. There are several challenges with modeling oxycodone abuse. First, prescription opioids including oxycodone are orally self-administered and have different pharmacokinetics and dynamics than morphine or fentanyl which have been more comm...

G protein coupled receptors (GPCRs) comprise over 17% of all approved drug targets, constituting the largest family of proteins targeted by currently available pharmaceutical treatments, including those for acute and chronic pain conditions. An important factor in inhibitory GPCR function is the activation of G protein-gated inwardly rectifying pot...

Remodeling of the nervous system serves as a protective mechanism during abrupt disturbance of neuronal homeostasis. This offers adequate maintenance of overall network activity that includes both synaptic scaling and regulation of intrinsic neuronal excitability in an adaptive process known as homeostatic plasticity. Although alterations in neuron...

Oxycodone is one of the most commonly prescribed analgesics for moderate to severe pain disorders. While effective in the short term, long-term use can result in a myriad of unwanted side-effects which include tolerance, physical dependence and the development of opioid use disorder. Δ9-Tetrahydrocannabinol (Δ9-THC), is a partial cannabinoid recept...

Differences in nociceptor physiology between humans and rodents is a major roadblock in the successful translation of preclinical analgesic targets to clinical therapy. Both acute and chronic inflammation by mediators like bradykinin (BK) has been implicated in the pathogenesis of pain. However, to date, few studies have examined how BK modulates t...

Activation of cannabinoid receptor type 1 (CB 1 ) produces analgesia in a variety of preclinical models of pain; however, engagement of central CB 1 receptors is accompanied by unwanted side effects, such as tolerance and dependence. Efforts to develop novel analgesics have focused on targeting peripheral CB 1 receptors to circumvent central CB 1 -...

Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side-effect of all major chemotherapeutic agents. Here, we explored efficacy of voluntary exercise as a nonpharmacological strategy for suppressing two distinct adverse side effects of chemotherapy treatment. We evaluated whether voluntary running would suppress both neurop...

Activation of cannabinoid CB 1 receptors suppresses pathological pain but also produces unwanted side effects, including tolerance and physical dependence. Inhibition of fatty-acid amide hydrolase (FAAH), the major enzyme catalyzing the degradation of anandamide (AEA), an endocannabinoid, and other fatty-acid amides, suppresses pain without unwante...

Opioid-based therapies remain a mainstay for chronic pain management, but unwanted side-effects limit therapeutic use. We compared efficacies of brain permeant and impermeant inhibitors of fatty-acid amide hydrolase (FAAH) in suppressing neuropathic pain induced by the chemotherapeutic agent paclitaxel. Paclitaxel produced mechanical and cold allod...

Fatty-acid amide hydrolase (FAAH) is the major enzyme responsible for degradation of anandamide, an endocannabinoid. Pharmacological inhibition or genetic deletion of FAAH (FAAH KO) produces antinociception in preclinical pain models that is largely attributed to anandamide-induced activation of cannabinoid receptors. However, FAAH metabolizes a wi...

Nicotinamide mononucleotide adenylyl transferases (NMNATs) are essential neuronal maintenance factors postulated to preserve neuronal function and protect against axonal degeneration in various neurodegenerative disease states. We used in vitro and in vivo approaches to assess the impact of NMNAT2 reduction on cellular and physiological functions i...

Mefloquine hydrochloride has been used widely in the past few decades for malaria prophylaxis and treatment. However, in recent years, it has fallen out of favor due to reports of exposure being linked to numerous neuropsychiatric effects, including emotional disturbances. In this study we examined the effects of different doses (5, 25, or 100 mg/...