Neuroanatomy of the nociceptive system: From nociceptors to brain networks.

This chapter reviews the neuroanatomy of the nociceptive system and its functional organization. We describe three main compartments of the nervous system that underlie normal nociception and the resulting pain percept: Peripheral, Spinal Cord, and Brain. We focus on how ascending nociceptive processing streams traverse these anatomical compartments, culminating in the multidimensional experience of pain.

It all began in Issaquah 50 years ago.

"Somehow scientists still pursue the same questions, if now on higher levels of theoretical abstraction rooted in deeper layers of empirical evidence… To paraphrase an old philosophy joke, science is more like it is today than it has ever been. In other words, science remains as challenging as ever to human inquiry. And the need to communicate its progress… remains as essential now as then.

Long-term optical imaging of the spinal cord in awake behaving mice.

Advances in optical imaging and fluorescent biosensors enable study of the spatiotemporal and long-term neural dynamics in the brain of awake animals. However, methodological difficulties and fibrosis limit similar advances in the spinal cord. Here, to overcome these obstacles, we combined in vivo application of fluoropolymer membranes that inhibit fibrosis, a redesigned implantable spinal imaging chamber and improved motion correction methods that together permit imaging of the spinal cord in awake behaving mice, for months to over a year.

Regulatory T cell-derived enkephalin gates nociception.

T cells have emerged as sex-dependent orchestrators of pain chronification but the sexually dimorphic mechanisms by which T cells control pain sensitivity is not resolved. Here, we demonstrate an influence of regulatory T cells (Tregs) on pain processing that is distinct from their canonical functions of immune regulation and tissue repair. Specifically, meningeal Tregs (mTregs) express the endogenous opioid, enkephalin, and mTreg-derived enkephalin exerts an antinociceptive action through a presynaptic opioid receptor signaling mechanism that is dispensable for immunosuppression.

Large library docking for cannabinoid-1 receptor agonists with reduced side effects.

Large library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking new agonists for the cannabinoid-1 receptor (CB1R), we docked 74 million tangible molecules, prioritizing 46 high ranking ones for de novo synthesis and testing. Nine were active by radioligand competition, a 20% hit-rate.

Docking for EP4R antagonists active against inflammatory pain.

The lipid prostaglandin E (PGE) mediates inflammatory pain by activating G protein-coupled receptors, including the prostaglandin E2 receptor 4 (EP4R). Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce nociception by inhibiting prostaglandin synthesis, however, the disruption of upstream prostanoid biosynthesis can lead to pleiotropic effects including gastrointestinal bleeding and cardiac complications. In contrast, by acting downstream, EP4R antagonists may act specifically as anti-inflammatory agents and, to date, no selective EP4R antagonists have been approved for human use.

International Association for the Study of Pain publications over the 50-year span.

The International Association for the Study of Pain (IASP) has a 50-year history of publishing educational and research materials, ranging from traditional print format books, journals, and other informational formats to online and electronic formats. Here we provide a historical overview of IASP publications and reflections from the perspective of 5 former or current Editors-in-Chief.

Functional imaging studies of acute administration of classic psychedelics, ketamine, and MDMA: Methodological limitations and convergent results.

Functional magnetic resonance imaging (fMRI) is increasingly used to non-invasively study the acute impact of psychedelics on the human brain. While fMRI is a promising tool for measuring brain function in response to psychedelics, it also has known methodological challenges. We conducted a systematic review of fMRI studies examining acute responses to experimentally administered psychedelics in order to identify convergent findings and characterize heterogeneity in the literature.

Pain and Itch Processing in Aged Mice.

Most reports agree that aging negatively impacts pain processing and that the prevalence of chronic pain increases significantly with age. To improve current therapies, it is critical that aged animals be included in preclinical studies. Here we compared sensitivities to pain and itch-provoking stimuli in naïve and injured young and aged mice.

Long-term optical imaging of the spinal cord in awake, behaving animals.

Advances in optical imaging approaches and fluorescent biosensors have enabled an understanding of the spatiotemporal and long-term neural dynamics in the brain of awake animals. However, methodological difficulties and the persistence of post-laminectomy fibrosis have greatly limited similar advances in the spinal cord. To overcome these technical obstacles, we combined application of fluoropolymer membranes that inhibit fibrosis; a redesigned, cost-effective implantable spinal imaging chamber; and improved motion correction methods that together permit imaging of the spinal cord in awake, behaving mice, for months to over a year.

Structure-based discovery of conformationally selective inhibitors of the serotonin transporter.

The serotonin transporter (SERT) removes synaptic serotonin and is the target of anti-depressant drugs. SERT adopts three conformations: outward-open, occluded, and inward-open. All known inhibitors target the outward-open state except ibogaine, which has unusual anti-depressant and substance-withdrawal effects, and stabilizes the inward-open conformation.

Paradoxical increases in anterior cingulate cortex activity during nitrous oxide-induced analgesia reveal a signature of pain affect.

The general consensus is that increases in neuronal activity in the anterior cingulate cortex (ACC) contribute to pain's negative affect. Here, using imaging of neuronal calcium dynamics in mice, we report that nitrous oxide, a general anesthetic that reduces pain affect, paradoxically, increases ACC spontaneous activity. As expected, a noxious stimulus also increased ACC activity.

Structure-based discovery of nonopioid analgesics acting through the α-adrenergic receptor.

Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α-adrenergic receptor (αAR), seeking new αAR agonists chemotypes that lack the sedation conferred by known αAR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential G and G signaling. Experimental structures of αAR complexed with two of these agonists confirmed the docking predictions and templated further optimization.

TRPV1 drugs alter core body temperature via central projections of primary afferent sensory neurons.

TRPV1, a capsaicin- and heat-activated ion channel, is expressed by peripheral nociceptors and has been implicated in various inflammatory and neuropathic pain conditions. Although pharmacological modulation of TRPV1 has attracted therapeutic interest, many TRPV1 agonists and antagonists produce thermomodulatory side effects in animal models and human clinical trials, limiting their utility. These on-target effects may result from the perturbation of TRPV1 receptors on nociceptors, which transduce signals to central thermoregulatory circuits and release proinflammatory factors from their peripheral terminals, most notably the potent vasodilative neuropeptide, calcitonin gene-related peptide (CGRP).

History of Spinal Cord "Pain" Pathways Including the Pathways Not Taken.

Traditional medical neuroanatomy/neurobiology textbooks teach that pain is generated by several ascending pathways that course in the anterolateral quadrant of the spinal cord, including the spinothalamic, spinoreticular and spinoparabrachial tracts. The textbooks also teach, building upon the mid-19th century report of Brown-Séquard, that unilateral cordotomy, namely section of the anterolateral quadrant, leads to contralateral loss of pain (and temperature). In many respects, however, this simple relationship has not held up.

Structural imaging studies of patients with chronic pain: an anatomical likelihood estimate meta-analysis.

Neuroimaging is a powerful tool to investigate potential associations between chronic pain and brain structure. However, the proliferation of studies across diverse chronic pain syndromes and heterogeneous results challenges data integration and interpretation. We conducted a preregistered anatomical likelihood estimate meta-analysis on structural magnetic imaging studies comparing patients with chronic pain and healthy controls.

ACVR1-activating mutation causes neuropathic pain and sensory neuron hyperexcitability in humans.

Altered bone morphogenetic protein (BMP) signaling is associated with many musculoskeletal diseases. However, it remains unknown whether BMP dysfunction has direct contribution to debilitating pain reported in many of these disorders. Here, we identified a novel neuropathic pain phenotype in patients with fibrodysplasia ossificans progressiva (FOP), a rare autosomal-dominant musculoskeletal disorder characterized by progressive heterotopic ossification.

Structure-Based Design of a Chemical Probe Set for the 5-HT Serotonin Receptor.

The 5-HT receptor (5-HTR), for which no selective agonists and a few antagonists exist, remains the least understood serotonin receptor. A single commercial antagonist, SB-699551, has been widely used to investigate the 5-HTR function in neurological disorders, including pain, but this molecule has substantial liabilities as a chemical probe. Accordingly, we sought to develop an internally controlled probe set.

Regulatory T-cells inhibit microglia-induced pain hypersensitivity in female mice.

Peripheral nerve injury-induced neuropathic pain is a chronic and debilitating condition characterized by mechanical hypersensitivity. We previously identified microglial activation via release of colony-stimulating factor 1 (CSF1) from injured sensory neurons as a mechanism contributing to nerve injury-induced pain. Here, we show that intrathecal administration of CSF1, even in the absence of injury, is sufficient to induce pain behavior, but only in male mice.

Pain and itch processing by subpopulations of molecularly diverse spinal and trigeminal projection neurons.

A remarkable molecular and functional heterogeneity of the primary sensory neurons and dorsal horn interneurons transmits pain- and or itch-relevant information, but the molecular signature of the projection neurons that convey the messages to the brain is unclear. Here, using retro-TRAP (translating ribosome affinity purification) and RNA sequencing, we reveal extensive molecular diversity of spino- and trigeminoparabrachial projection neurons. Among the many genes identified, we highlight distinct subsets of -, -, -, and -expressing projection neurons.

Contribution of dorsal horn CGRP-expressing interneurons to mechanical sensitivity.

Primary sensory neurons are generally considered the only source of dorsal horn calcitonin gene-related peptide (CGRP), a neuropeptide critical to the transmission of pain messages. Using a tamoxifen-inducible transgenic mouse, here we identified a distinct population of CGRP-expressing excitatory interneurons in lamina III of the spinal cord dorsal horn and trigeminal nucleus caudalis. These interneurons have spine-laden, dorsally directed, dendrites, and ventrally directed axons.