Pharmacology/Drug Development

Toll like receptor 9 (TLR9) is a critical sensor for danger-associated molecular patterns (DAMPs) and a crucial marker of non-sterile/sterile inflammation among all TLRs. However, the significance of TLR9 in inflammatory pain remains unclear. Here, we subcutaneously injected Complete Freund's adjuvant (CFA) into the plantar surface of the hind paw, to established a mouse model of inflammatory pain, and we examined expression and distribution of TLR9 in this model. There was a significant increase of TLR9 mRNA and reduction of mechanical paw withdrawal threshold in mice intraplantar injected with CFA. By contrast, mechanical paw withdrawal threshold significantly increased in mice treated with TLR9 antagonist ODN2088. Furthermore, TLR9 is found predominantly distributed in the neurons by immunofluorescence experiment. Accordingly, neuronal TLR9 downregulation in the spinal cord prevented CFA-induced persistent hyperalgesia. Overall, these findings indicate that neuronal TLR9 in the spinal cord is closely related to CFA-induced inflammatory pain. It provides a potential treatment option for CFA-induced inflammatory pain by applying TLR9 antagonist.

Fibromyalgia is a chronic neurological condition characterized by widespread pain. The effectiveness of current pharmacological treatments is limited. However, several medications have been approved for phase IV trials in order to evaluate them. To identify and provide details of drugs that have been tested in completed phase IV clinical trials for fibromyalgia management in adults, including the primary endpoints and treatment outcomes. This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology. Publicly available and relevant phase IV trials registered at ClinicalTrials.gov were analyzed. The uses of the trialed drugs for fibromyalgia were reviewed. As of 8 August 2022, a total of 1,263 phase IV clinical trials were identified, of which 121 were related to fibromyalgia. From these, 10 clinical trials met the inclusion criteria for the current study. The drugs used in phase IV trials are milnacipran, duloxetine, pregabalin, a combination of tramadol and acetaminophen, and armodafinil. The effectiveness of the current pharmacological treatments is apparently limited. Due to its complexity and association with other functional pain syndromes, treatment options for fibromyalgia only are limited and they are designed to alleviate the symptoms rather than to alter the pathological pathway of the condition itself. Pain management specialists have numerous pharmacologic options available for the management of fibromyalgia.

Recent studies showed promotion of astrocyte autophagy in the spinal cord would provide analgesic effects. Silent information regulator T1 (SIRT1) and α subunit of peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1α) are two master regulators of endogenous antioxidant defense and mitochondrial biogenesis. They play vital roles in both autophagy and neuropathic pain (NP). Our previous study showed that TSPO agonist Ro5-4864 elicited potent analgesic effects against NP, but the mechanisms remain unclear. This study aims to investigate the effects of TSPO agonist Ro5-4864 on autophagy and nuclear SIRT1/PGC-1α signaling in spinal dorsal horn.

Nerve Growth Factor (NGF) is a pivotal mediator of chronic pain and plays a role in bone remodelling. Through its high affinity receptor TrkA, NGF induces substance P (SP) as key downstream mediator of pain and local inflammation. Here we analysed NGF, TrkA and SP tissue distribution in facet joint osteoarthritis (FJOA), a major cause of chronic low back pain.

Morphine and its substitutes are frequently used in the clinical treatment of acute severe pain and advanced cancer patients. Long-term irregular use of morphine will lead to severe dependence. However, the genes behind the analgesic and addictive effects of morphine still need to be revealed.

Atopic dermatitis (AD), driven by interleukins (IL-4/IL-13), is a chronic inflammatory skin disease characterized by intensive pruritus. However, it is unclear how immune signaling and sensory response pathways cross talk with each other. We differentiated itch sensory neuron-like cells (ISNLCs) from iPSC lines. These ISNLCs displayed neural markers and action potentials and responded specifically to itch-specific stimuli. These ISNLCs expressed receptors specific for IL-4/IL-13 and were activated directly by the two cytokines. We successfully innervated these ISNLCs into full thickness human skin constructs. These innervated skin grafts can be used in clinical applications such as wound healing. Moreover, the availability of such innervated skin models will be valuable to develop drugs to treat skin diseases such as AD.

Cannabidiol (CBD) products are available nearly nationwide in the US and can coexist with medical or recreational programs. North Carolina (NC) is an example of a state with a program dedicated to integrating hemp cultivation and medicinal CBD exclusively, containing a multitude of retailers selling it as a primary product. The Food and Drug Administration (FDA) mandates that non-FDA approved CBD products cannot be marketed using medical or health-related claims and has sent warning letters to retailers violating these terms. We aim to characterize the online content of the NC CBD market by analyzing retailers' websites to determine whether hemp/CBD shops comply with FDA regulations in terms of medical claims and analyze the claimed CBD content and price of products offered online.

Glutamate is the principal excitatory neurotransmitter in the central nervous system. In the periphery, glutamate acts as a transmitter and involves in the signaling and processing of sensory input. Glutamate acts at several types of receptors and also interacts with other transmitters/mediators under various physiological and pathophysiological conditions including chronic pain. The increasing amount of evidence suggests that glutamate may play a role through multiple mechanisms in orofacial pain processing. In this study, we reviewed the current understanding of how peripheral glutamate mediates orofacial pain, how glutamate is regulated in the periphery, and how these findings are translated into therapies for pain conditions.

Menthol is an important flavoring additive that triggers a cooling sensation. Under physiological condition, low to moderate concentrations of menthol activate transient receptor potential cation channel subfamily M member 8 (TRPM8) in the primary nociceptors, such as dorsal root ganglion (DRG) and trigeminal ganglion, generating a cooling sensation, whereas menthol at higher concentration could induce cold allodynia, and cold hyperalgesia mediated by TRPM8 sensitization. In addition, the paradoxical irritating properties of high concentrations of menthol is associated with its activation of transient receptor potential cation channel subfamily A member 1 (TRPA1). Under pathological situation, menthol activates TRPM8 to attenuate mechanical allodynia and thermal hyperalgesia following nerve injury or chemical stimuli. Recent reports have recapitulated the requirement of central group II/III metabotropic glutamate receptors (mGluR) with endogenous κ-opioid signaling pathways for menthol analgesia. Additionally, blockage of sodium channels and calcium influx is a determinant step after menthol exposure, suggesting the possibility of menthol for pain management. In this review, we will also discuss and summarize the advances in menthol-related drugs for pathological pain treatment in clinical trials, especially in neuropathic pain, musculoskeletal pain, cancer pain and postoperative pain, with the aim to find the promising therapeutic candidates for the resolution of pain to better manage patients with pain in clinics.