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Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) may play an important role in primary headaches. Preclinical evidence suggests that PACAP38 modulates trigeminal nociceptive activity mainly through PAC1 receptors while clinical studies report that plasma concentrations of PACAP38 are elevated in spontaneous attacks of cluster headache and migraine and normalize after treatment with sumatriptan. Intravenous infusion of PACAP38 induces migraine-like attacks in migraineurs and cluster-like attacks in cluster headache patients. A rodent-specific PAC1 receptor antibody Ab181 was developed and its effect on nociceptive neuronal activity in the trigeminocervical complex was investigated in vivo in an electrophysiological model relevant to primary headaches. Ab181 is potent and selective at the rat PAC1 receptor and provides near maximum target coverage at 10 mg/kg for more than 48 hours. Without affecting spontaneous neuronal activity, Ab181 effectively inhibits stimulus-evoked activity in the trigeminocervical complex. Immunohistochemical analysis revealed its binding in the trigeminal ganglion and sphenopalatine ganglion but not within the CNS suggesting a peripheral site of action. The pharmacological approach using a specific PAC1 receptor antibody could provide a novel mechanism with a potential clinical efficacy in the treatment of primary headaches.
Learn More >Experimental and clinical data strongly support vagus nerve stimulation (VNS) as a novel treatment in migraine. VNS acutely suppresses cortical spreading depression (CSD) susceptibility, an experimental model that has been used to screen for migraine therapies. However, mechanisms underlying VNS efficacy on CSD are unknown. Here, we interrogated the central and peripheral mechanisms using VNS delivered either invasively (iVNS) or non-invasively (nVNS) in male Sprague-dawley rats. CSD susceptibility was evaluated 40 min after the stimulation. iVNS elevated the electrical CSD threshold more than two-fold and decreased KCl-induced CSD frequency by 22% when delivered to intact vagus nerve. Distal vagotomy did not alter iVNS efficacy (2-fold higher threshold and 19% lower frequency in iVNS vs. sham). In contrast, proximal vagotomy completely abolished iVNS effect on CSD. Pharmacological blockade of nucleus tractus solitarius (NTS), the main relay for vagal afferents, by lidocaine or glutamate receptor antagonist CNQX also prevented CSD suppression by nVNS. Supporting a role for both norepinephrine and serotonin, CSD suppression by nVNS was inhibited by more than 50% after abrogating norepinephrinergic or serotonergic neurotransmission alone using specific neurotoxins; abrogating both completely blocked the nVNS effect. Our results suggest that VNS inhibits CSD through central afferents relaying in NTS and projecting to subcortical neuromodulatory centers providing serotonergic and norepinephrinergic innervation to the cortex.
Learn More >Cold allodynia is often seen in the acute phase of oxaliplatin treatment, but the underlying pathophysiology remains unclear.
Learn More >The signs and symptoms of persistent temporomandibular joint (TMJ)/muscle disorder (TMJD) pain suggest the existence of a central neural dysfunction or a problem of pain amplification. The etiology of chronic TMJD is not known; however, female sex hormones have been identified as significant risk factors. Converging lines of evidence indicate that the junctional region between the trigeminal subnucleus caudalis (Vc) and the upper cervical spinal cord, termed the Vc/C1-2 region, is the primary site for the synaptic integration of sensory input from TMJ nociceptors. In this paper, the mechanisms behind the estrogen effects on the processing of nociceptive inputs by neurons in the Vc/C1-2 region reported by human and animal studies are reviewed. The Vc/C1-2 region has direct connections to endogenous pain and autonomic control pathways, which are modified by estrogen status and are suggested to be critical for somatomotor and autonomic reflex responses of TMJ-related sensory signals.
Learn More >Transient receptor potential channel subfamily A member 1 (TRPA1) is a Ca-permeable cation channel that serves as one of the primary sensors of environmental irritants and noxious substances. Many TRPA1 agonists are electrophiles that are recognized by TRPA1 via covalent bond modifications of specific cysteine residues located in the cytoplasmic domains. However, a mechanistic understanding of electrophile sensing by TRPA1 has been limited due to a lack of high-resolution structural information. Here, we present the cryoelectron microscopy (cryo-EM) structures of nanodisc-reconstituted ligand-free TRPA1 and TRPA1 in complex with the covalent agonists JT010 and BITC at 2.8, 2.9, and 3.1 Å, respectively. Our structural and functional studies provide the molecular basis for electrophile recognition by the extraordinarily reactive C621 in TRPA1 and mechanistic insights into electrophile-dependent conformational changes in TRPA1. This work also provides a platform for future drug development targeting TRPA1.
Learn More >Sickle cell disease (SCD), one of the most common inherited disorders, is associated with vaso-occlusive pain episodes and haemolysis leading to recurrent morbidity, hospital admissions and work or school absenteeism. The crises are conventionally treated with opioids, non-opioids and other adjuvants with the risk of developing complications, addictions and drug-seeking behaviour. Different non-pharmacological treatments, such as transcutaneous electrical nerve stimulation (TENS) have been used for managing pain in other painful conditions. Hence, the efficacy of TENS for managing pain in SCD needs to be reviewed.
Learn More >As many as one third of patients undergoing minimally invasive thoracic surgery and one half undergoing thoracotomy develop chronic pain, defined as pain lasting 2-3 months. There is limited information regarding predictors of chronic pain and even less is known about its impact on health-related quality of life, known as pain interference. Currently, there is a focus on decreased opioid prescribing after surgery. Interestingly thoracic surgical patients are the least likely to be on opioids before surgery and have the highest rate of new persistent opioid use after surgery compared to other surgical cohorts. These studies of opioid use have identified important predictors of new persistent opioid use, but their findings are limited by failing to correlate opioid use with pain. The objectives of this invited review are to present the findings of pertinent studies of chronic pain and opioid use after thoracic surgery, "where we are", and to discuss gaps in our knowledge of these topics and opportunities for research to fill those gaps, "where we need to go".
Learn More >Gastrin-releasing peptide (GRP) receptor-expressing (GRPR) neurons have a central role in the spinal transmission of itch. Because their fundamental regulatory mechanisms are not yet understood, it is important to determine how such neurons are excited and integrate itch sensations. In this study, we investigated the mechanisms for the activation of itch-responsive GRPR neurons in the spinal dorsal horn (SDH). GRPR neurons expressed the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) containing the GluR2 subunit. In mice, peripherally elicited histaminergic and non-histaminergic itch was prevented by intrathecal (i.t.) administration of the AMPAR antagonist NBQX, which was consistent with the fact that firing of GRPR neurons in SDH under histaminergic and non-histaminergic itch was completely blocked by NBQX, but not by the GRPR antagonist RC-3095. Because GRP neurons in SDH contain glutamate, we investigated the role of GRP (GRP/Glu) neurons in regulating itch. Chemogenetic inhibition of GRP neurons suppressed both histaminergic and non-histaminergic itch without affecting the mechanical pain threshold. In nonhuman primates, i.t. administration of NBQX also attenuated peripherally elicited itch without affecting the thermal pain threshold. In a mouse model of diphenylcyclopropenone (DCP)-induced contact dermatitis, GRP, GRPR, and AMPAR subunits were upregulated in SDH. DCP-induced itch was prevented by either silencing GRP neurons or ablation of GRPR neurons. Altogether, these findings demonstrate that GRP and glutamate cooperatively regulate GRPR AMPAR neurons in SDH, mediating itch sensation. GRP-GRPR and the glutamate-AMPAR system may play pivotal roles in the spinal transmission of itch in rodents and nonhuman primates.
Learn More >Effective, non-addictive therapeutics for chronic pain remain a critical need. While there are several potential therapeutics that stimulate anti-inflammatory mechanisms to restore homeostasis in the spinal dorsal horn microenvironment, the effectiveness of drugs for neuropathic pain are still inadequate. The convergence of increasing knowledge about the multi-factorial mechanisms underlying neuropathic pain and the mechanisms of drug action from preclinical studies are providing the ability to create pharmaceuticals with better clinical effectiveness. By targeting and activating the peroxisome proliferator-activated receptor gamma subunit (PPARγ), numerous preclinical studies report pleiotropic effects of thiazolidinediones (TDZ) beyond their intended use of increasing insulin, including their anti-inflammatory, renal, cardioprotective, and oncopreventative effects. Several studies find TDZs reduce pain-related behavioral symptoms, including ongoing secondary hypersensitivity driven by central sensitization. Previous studies find increased PPARγ in the spinal cord and brain regions innervated by incoming afferent nerve endings after the induction of neuropathic pain models. PPARγ agonist treatment provides an effective reduction in pain-related behaviors, including anxiety. Data further suggest that improved brain mitochondrial bioenergetics after PPARγ agonist treatment is a key mechanism for reducing hypersensitivity. This review emphasizes two points relevant for the development of better chronic pain therapies. First, employing neuropathic pain models with chronic duration is critical since they can encompass the continuum of molecular and brain circuitry alterations arising over time when pain persists, providing greater relevance to clinical pain syndromes. Assisting in that effort are preclinical models of chronic trigeminal pain syndromes. Secondly, considering the access to nerve and brain neurons and glia across the blood-brain barrier is important. While many therapies have low brain penetrance, a PPARγ agonist with better brain penetrance, ELB00824, has been developed. Purposeful design and recent comparative testing indicate that ELB00824 is extraordinarily efficient and efficacious. ELB00824 provides greatly improved attenuation of pain-related behaviors, including mechanical hypersensitivity, anxiety, and depression in our chronic trigeminal nerve injury models. Physiochemical properties allowing significant brain access and toxicity testing are discussed.
Learn More >This proof-of-concept study demonstrates and validates a novel approach that automatically translates information derived from patient reported outcome measures (PROMs) into a standardized functioning report based on the International Classification of Functioning, Disability and Health (ICF).
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