Opioid circuit opens path to pain relief.

Manipulation of neural circuits targeted by morphine enables pain relief without opioids.

The 'in's and out's' of descending pain modulation from the rostral ventromedial medulla.

The descending-pain modulating circuit controls the experience of pain by modulating transmission of sensory signals through the dorsal horn. This circuit's key output node, the rostral ventromedial medulla (RVM), integrates 'top-down' and 'bottom-up' inputs that regulate functionally defined RVM cell types, 'OFF-cells' and 'ON-cells', which respectively suppress or facilitate pain-related sensory processing. While recent advances have sought molecular definition of RVM cell types, conflicting behavioral findings highlight challenges involved in aligning functional and molecularly defined types.

The potential role of chronic pain and the polytrauma clinical triad in predicting prodromal PD: A cross-sectional study of U.S. Veterans.

Introduction: The research criteria for prodromal Parkinson disease (pPD) depends on prospectively validated clinical inputs with large effect sizes and/or high prevalence. Neither traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), nor chronic pain are currently included in the calculator, despite recent evidence of association with pPD. These conditions are widely prevalent, co-occurring, and already known to confer risk of REM behavior disorder (RBD) and PD.

CFA-treated mice induce hyperalgesia in healthy mice via an olfactory mechanism.

Background: Social interactions with subjects experiencing pain can increase nociceptive sensitivity in observers, even without direct physical contact. In previous experiments, extended indirect exposure to soiled bedding from mice with alcohol withdrawal-related hyperalgesia enhanced nociception in their conspecifics. This finding suggested that olfactory cues could be sufficient for nociceptive hypersensitivity in otherwise untreated animals (also known as "bystanders").

Direct and Indirect Nociceptive Input from the Trigeminal Dorsal Horn to Pain-Modulating Neurons in the Rostral Ventromedial Medulla.

The brain is able to amplify or suppress nociceptive signals by means of descending projections to the spinal and trigeminal dorsal horns from the rostral ventromedial medulla (RVM). Two physiologically defined cell classes within RVM, "ON-cells" and "OFF-cells," respectively facilitate and inhibit nociceptive transmission. However, sensory pathways through which nociceptive input drives changes in RVM cell activity are only now being defined.

Brainstem pain-modulating neurons are sensitized to visual light in persistent inflammation.

Many individuals with chronic pain report abnormal sensitivity to visual light, referred to as "photosensitivity" or "photophobia," yet how processing of light and nociceptive information come together remains a puzzle. Pain-modulating neurons in the rostral ventromedial medulla (RVM) have been shown to respond to bright visual light in male rats: activity of pain-enhancing ON-cells is increased, while that of pain-inhibiting OFF-cells is decreased. Since the RVM is the output node of a well-known pain modulation pathway, light-related input to these neurons could contribute to photosensitivity.

Shifting the Balance: How Top-Down and Bottom-Up Input Modulate Pain the Rostral Ventromedial Medulla.

The sensory experience of pain depends not only on the transmission of noxious information (nociception), but on the state of the body in a biological, psychological, and social milieu. A brainstem pain-modulating system with its output node in the rostral ventromedial medulla (RVM) can regulate the threshold and gain for nociceptive transmission. This review considers the current understanding of how RVM pain-modulating neurons, namely ON-cells and OFF-cells, are engaged by "top-down" cognitive and emotional factors, as well as by "bottom-up" sensory inputs, to enhance or suppress pain.

Photosensitivity Is Associated with Chronic Pain following Traumatic Brain Injury.

Individuals with a history of traumatic brain injury (TBI) report increased rates of chronic pain. Photosensitivity is also a common chronic symptom following TBI and is prevalent among other types of chronic pain. The aim of this study was to better understand the relationship between chronic pain, pain-related disability, and photosensitivity in a TBI population.

Physiological properties of pain-modulating neurons in rostral ventromedial medulla in female rats, and responses to opioid administration.

Functional pain disorders disproportionately impact females, but most pain research in animals has been conducted in males. While there are anatomical and pharmacological sexual dimorphisms in brainstem pain-modulation circuits, the physiology of pain-modulating neurons that comprise a major functional output, the rostral ventromedial medulla (RVM), has not been explored in female animals. The goal of this study was to identify and characterize the activity of RVM cells in female, compared to male, rats.

Different Methods for Traumatic Brain Injury Diagnosis Influence Presence and Symptoms of Post-Concussive Syndrome in United States Veterans.

Common methods for evaluating history of traumatic brain injury (TBI) include self-report, electronic medical record review (EMR), and structured interviews such as the Head Trauma Events Characteristics (HTEC). Each has strengths and weaknesses, but little is known regarding how TBI diagnostic rates or the associated symptom profile differ among them. This study examined 200 Veterans recruited within the VA Portland Health Care System, each evaluated for TBI using self-report, EMR, and HTEC.

Parabrachial Complex: A Hub for Pain and Aversion.

The parabrachial nucleus (PBN) has long been recognized as a sensory relay receiving an array of interoceptive and exteroceptive inputs relevant to taste and ingestive behavior, pain, and multiple aspects of autonomic control, including respiration, blood pressure, water balance, and thermoregulation. Outputs are known to be similarly widespread and complex. How sensory information is handled in PBN and used to inform different outputs to maintain homeostasis and promote survival is only now being elucidated.

From Pleasure to Pain, and Back Again: The Intricate Relationship Between Alcohol and Nociception.

Aims: A close and bidirectional relationship between alcohol consumption and pain has been previously reported and discussed in influential reviews. The goal of the present narrative review is to provide an update on the developments in this field in order to guide future research objectives.

Methods: We evaluated both epidemiological and neurobiological literature interrogating the relationship between alcohol use and pain for the presence of significant effects.

Descending Control Mechanisms and Chronic Pain.

Purpose Of Review: The goal of the review was to highlight recent advances in our understanding of descending pain-modulating systems and how these contribute to persistent pain states, with an emphasis on the current state of knowledge around "bottom-up" (sensory) and "top-down" (higher structures mediating cognitive and emotional processing) influences on pain-modulating circuits.

Recent Findings: The connectivity, physiology, and function of these systems have been characterized extensively over the last 30 years. The field is now beginning to ask how and when these systems are engaged to modulate pain.

Plasticity in the Link between Pain-Transmitting and Pain-Modulating Systems in Acute and Persistent Inflammation.

There is strong evidence that spinoparabrachial neurons in the superficial dorsal horn contribute to persistent pain states, and that the lateral parabrachial complex (PB) conveys relevant nociceptive information to higher structures. The role of PB itself in hyperalgesia and how it recruits descending facilitation has nevertheless received significantly less attention. The current study is a first step toward delineating the functional dynamics of PB and its link to descending control in acute and persistent inflammatory pain.

Increased Sleep Disturbances and Pain in Veterans With Comorbid Traumatic Brain Injury and Posttraumatic Stress Disorder.

Study Objectives: Veterans are at an increased risk for traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD), both of which are associated with sleep disturbances and increased pain. Furthermore, sleep disturbances and pain are reciprocally related such that each can exacerbate the other. Although both TBI and PTSD are independently linked to sleep disturbances and pain, it remains unclear whether Veterans with comorbid TBI+PTSD show worse sleep disturbances and pain compared to those with only TBI or PTSD.

Anterior Cingulate Cortex Contributes to Alcohol Withdrawal- Induced and Socially Transferred Hyperalgesia.

Pain is often described as a "biopsychosocial" process, yet social influences on pain and underlying neural mechanisms are only now receiving significant experimental attention. Expression of pain by one individual can be communicated to nearby individuals by auditory, visual, and olfactory cues. Conversely, the perception of another's pain can lead to physiological and behavioral changes in the observer, which can include induction of hyperalgesia in "bystanders" exposed to "primary" conspecifics in which hyperalgesia has been induced directly.

Optogenetic Evidence for a Direct Circuit Linking Nociceptive Transmission through the Parabrachial Complex with Pain-Modulating Neurons of the Rostral Ventromedial Medulla (RVM).

The parabrachial complex (PB) is a functionally and anatomically complex structure involved in a range of homeostatic and sensory functions, including nociceptive transmission. There is also evidence that PB can engage descending pain-modulating systems, the best characterized of which is the rostral ventromedial medulla (RVM). Two distinct classes of RVM neurons, "ON-cells" and "OFF-cells," exert net pronociceptive and anti-nociceptive effects, respectively.

Social transfer of pain in mice.

A complex relationship exists between the psychosocial environment and the perception and experience of pain, and the mechanisms of the social communication of pain have yet to be elucidated. The present study examined the social communication of pain and demonstrates that "bystander" mice housed and tested in the same room as mice subjected to inflammatory pain or withdrawal from morphine or alcohol develop corresponding hyperalgesia. Olfactory cues mediate the transfer of hyperalgesia to the bystander mice, which can be measured using mechanical, thermal, and chemical tests.

Parabrachial complex links pain transmission to descending pain modulation.

The rostral ventromedial medulla (RVM) has a well-documented role in pain modulation and exerts antinociceptive and pronociceptive influences mediated by 2 distinct classes of neurons, OFF-cells and ON-cells. OFF-cells are defined by a sudden pause in firing in response to nociceptive inputs, whereas ON-cells are characterized by a "burst" of activity. Although these reflex-related changes in ON- and OFF-cell firing are critical to their pain-modulating function, the pathways mediating these responses have not been identified.

Pain Modulation and the Transition from Acute to Chronic Pain.

There is now increasing evidence that pathological pain states are at least in part driven by changes in the brain itself. Descending modulatory pathways are known to mediate top-down regulation of nociceptive processing, transmitting cortical and limbic influences to the dorsal horn. However, these modulatory pathways are also intimately intertwined with ascending transmission pathways through positive and negative feedback loops.

A possible neural mechanism for photosensitivity in chronic pain.

Patients with functional pain disorders often complain of generalized sensory hypersensitivity, finding sounds, smells, or even everyday light aversive. The neural basis for this aversion is unknown, but it cannot be attributed to a general increase in cortical sensory processing. Here, we quantified the threshold for aversion to light in patients with fibromyalgia, a pain disorder thought to reflect dysregulation of pain-modulating systems in the brain.

Adaptations in responsiveness of brainstem pain-modulating neurons in acute compared with chronic inflammation.

Despite similar behavioral hypersensitivity, acute and chronic pain have distinct neural bases. We used intraplantar injection of complete Freund's adjuvant to directly compare activity of pain-modulating neurons in the rostral ventromedial medulla (RVM) in acute vs chronic inflammation. Heat-evoked and von Frey-evoked withdrawal reflexes and corresponding RVM neuronal activity were recorded in lightly anesthetized animals either during the first hour after complete Freund's adjuvant injection (acute) or 3 to 10 days later (chronic).