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. We recently showed that indirect inputs from the dorsal horn via the parabrachial complex (PB) convey nociceptive information to RVM. The purpose of the present study was to determine whether there are also direct dorsal horn inputs to RVM pain-modulating neurons. We focused on the trigeminal dorsal horn, which conveys sensory input from the face and head, and used a combination of single-cell recording with optogenetic activation and inhibition of projections to RVM and PB from the trigeminal interpolaris-caudalis transition zone (Vi/Vc) in male and female rats. We determined that a direct projection from ventral Vi/Vc to RVM carries nociceptive information to RVM pain-modulating neurons. This projection included a GABAergic component, which could contribute to nociceptive inhibition of OFF-cells. This approach also revealed a parallel, indirect, relay of trigeminal information to RVM via PB. Activation of the indirect pathway through PB produced a more sustained response in RVM compared with activation of the direct projection from Vi/Vc. These data demonstrate that a direct trigeminal output conveys nociceptive information to RVM pain-modulating neurons with a parallel indirect pathway through the parabrachial complex.SIGNIFICANCE STATEMENT Rostral ventromedial medulla (RVM) pain-modulating neurons respond to noxious stimulation, which implies that they receive input from pain-transmission circuits. However, the traditional view has been that there is no direct input to RVM pain-modulating neurons from the dorsal horn, and that nociceptive information is carried by indirect pathways. Indeed, we recently showed that noxious information can reach RVM pain-modulating neurons via the parabrachial complex (PB). Using in vivo electrophysiology and optogenetics, the present study identified a direct relay of nociceptive information from the trigeminal dorsal horn to physiologically identified pain-modulating neurons in RVM. Combined tracing and electrophysiology data revealed that the direct projection includes GABAergic neurons. Direct and indirect pathways may play distinct functional roles in recruiting pain-modulating neurons.

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. In lightly anesthetized rats, we recorded behavioral withdrawal evoked by mechanical stimulation of the hindpaw and, simultaneously, the activity of identified pain-modulating neurons, "ON-cells" and "OFF-cells," in the rostral ventromedial medulla (RVM). This was done before and after the inactivation of PB, contralateral or ipsilateral to an inflamed paw [1 h, 1 d, or 5-6 d after intraplantar injection of Complete Freund's Adjuvant (CFA)]. The inactivation of contralateral, but not ipsilateral, PB interfered with nociceptive input to RVM under basal conditions, as well as in acute inflammation. By contrast, blocking ipsilateral, but not contralateral, PB in established inflammation interfered with behavioral hyperalgesia and ON-cell and OFF-cell responses. The lesioning of contralateral PB before CFA injection prevented this recruitment of ipsilateral PB in persistent inflammation. These experiments show that contralateral PB is required to initiate hyperalgesia, which is then maintained by ipsilateral PB, most likely in both cases via the engagement of pain-modulating neurons of the RVM.SIGNIFICANCE STATEMENT The lateral parabrachial complex (PB) relays nociceptive information to brain circuits that are important for the transmission and modulation of pain, but its specific role in persistent pain and engagement of descending control mechanisms has received relatively little attention. We show here that PB contralateral and ipsilateral to an inflammatory insult demonstrate different functions as inflammation persists, likely by engaging pain-facilitating neurons of the rostral ventromedial medulla. While the contralateral PB, the target of the major spinoparabrachial pathway, relays acute nociceptive information, the ipsilateral PB is recruited or unmasked in persistent inflammation to maintain hyperalgesia. These data point to plasticity in the PB itself or its direct and indirect connections with pain-modulating systems as central to the development and maintenance of persistent pain.

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. With a focus on taste and ingestive behaviors, pain, and thermoregulation, this review is intended to provide a context for analysis of PBN circuits involved in aversion and avoidance, and consider how information of various modalities, interoceptive and exteroceptive, is processed within PBN and transmitted to distinct targets to signal challenge, and to engage appropriate behavioral and physiological responses to maintain homeostasis.

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. A recent focus is on the parabrachial complex, now recognized as the major relay of nociceptive information to pain-modulating circuits, and plasticity in this circuit and its connections to the RVM is marked in persistent inflammatory pain. Top-down influences from higher structures, including hypothalamus, amygdala, and medial prefrontal areas, are also considered. The challenge will be to tease out mechanisms through which a particular behavioral context engages distinct circuits to enhance or suppress pain, and to understand how these mechanisms contribute to chronic pain.

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. We outlined studies on interactions between alcohol use and pain using both self-reports and objective experimental measures and discussed potential underlying mechanisms of these interactions. RESULTS: Epidemiological, preclinical and clinical literature point to three major interactions between alcohol use and pain: (a) alcohol use leading to hyperalgesia, (b) alcohol use moderating pain and hyperalgesia and (c) chronic pain as a risk factor predisposing to alcohol relapse. Neurobiological studies using animal models to assess these interactions have transitioned from mostly involuntary modes of experimenter-controlled alcohol administration to self-administration procedures, and increasingly indicate that neuronal circuits implicated in both withdrawal and anticipation stages of alcohol use disorder also have a role in chronic pain. Mechanistically, alterations in GABA, glutamate, the corticotropin-releasing factor system, endogenous opioids and protein kinase C appear to play crucial roles in this maladaptive overlap. CONCLUSIONS: Many of the principles explaining the interactions between alcohol and pain remain on a strong foundation, but continuing progress in modeling these interactions and underlying systems will provide a clearer basis for understanding, and ultimately treating, the damaging aspects of this interaction.

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. Models of persistent pain that fail to include descending modulatory pathways are thus incomplete. Although teasing out individual links in a recurrent network is never straightforward, it is imperative that understanding of pain modulation be fully integrated into how we think about pain.

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. This review summarizes current understanding, derived primarily from rodent studies but with corroborating evidence from human imaging, of the role of RVM populations in pain modulation and persistent pain states and explores recent advances outlining inputs to, and outputs from, RVM pain-modulating neurons.

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"). AIM: The current study addressed this possibility using an inflammation-based hyperalgesia model and long- and short-term exposure paradigms in C57BL/6J mice. MATERIALS & METHOD: Adult male and female mice received intraplantar injection of complete Freund's adjuvant (CFA) and were used as stimulus animals to otherwise naïve same-sex bystander mice (BS). Another group of untreated mice (OLF) was simultaneously exposed to the bedding of the stimulus mice. RESULTS: In the long-term, 15-day exposure paradigm, the presence of CFA mice or their bedding resulted in reduced von Frey threshold but not Hargreaves paw withdrawal latency in BS or OLF mice. In the short-term paradigm, 1-hr interaction with CFA conspecifics or 1-hr exposure to their bedding induced mechanical hypersensitivity in BS and OLF mice lasting for 3 hrs. Chemical ablation of the main olfactory epithelium prevented bedding-induced and stimulus mice-induced mechanical hypersensitivity. Gas chromatography-mass spectrometry (GC-MS) analysis of the volatile compounds in the bedding of experimental mice revealed that CFA-treated mice released an increased number of compounds indicative of disease states. DISCUSSION AND CONCLUSION: These results demonstrate that CFA-induced inflammatory pain can modulate nociception in bystander mice via an olfactory mechanism involving dynamic changes in volatile compounds detectable in the rodent bedding. SIGNIFICANCE: Social context can influence nociceptive sensitivity. Recent studies suggested involvement of olfaction in this influence. In agreement with this idea, the present study shows that the presence of mice with inflammatory pain produces nociceptive hypersensitivity in nearby conspecifics. This enhanced nociception occurs via olfactory cues present in the mouse bedding. Analysis of the bedding from mice with inflammatory pain identifies a number of compounds indicative of disease states. These findings demonstrate the importance of olfactory system in influencing pain states.

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. Few studies have examined PD risk in the context of TBI and PTSD; none have examined chronic pain. This study aimed to measure the risk of pPD caused by TBI, PTSD, and chronic pain. Methods: 216 US Veterans were enrolled who had self-reported recurrent or persistent pain for at least three months. Of these, 44 met criteria for PTSD, 39 for TBI, and 41 for all three conditions. Several pain, sleep, affective, and trauma questionnaires were administered. Participants' history of RBD was determined via self-report, with a subset undergoing confirmatory video polysomnography. Results: A greater proportion of Veterans with chronic pain met criteria for RBD (36 % vs. 10 %) and pPD (18.0 % vs. 8.3 %) compared to controls. Proportions were increased in RBD (70 %) and pPD (27 %) when chronic pain co-occurred with TBI and PTSD. Partial effects were seen with just TBI or PTSD alone. When analyzed as continuous variables, polytrauma symptom severity correlated with pPD probability (r = 0.28, P = 0.03). Conclusion: These data demonstrate the potential utility of chronic pain, TBI, and PTSD in the prediction of pPD, and the importance of trauma-related factors in the pathogenesis of PD.

Deep brain stimulation entrains local neuronal firing in human globus pallidus internus.

Deep brain stimulation (DBS) in the internal segment of the globus pallidus (GPi) relieves the motor symptoms of Parkinson's disease, yet the mechanism of action remains uncertain. To address the question of how therapeutic stimulation changes neuronal firing in the human brain, we studied the effects of GPi stimulation on local neurons in unanesthetized patients. Eleven patients with idiopathic Parkinson's disease consented to participate in neuronal recordings during stimulator implantation surgery. A recording microelectrode and a DBS macroelectrode were advanced through the GPi in parallel until a single neuron was isolated. After a baseline period, stimulation was initiated with varying voltages and different stimulation sites. The intra-operative stimulation parameters (1-8 V, 88-180 Hz, 0.1-ms pulses) were comparable with the postoperative DBS settings. Stimulation in the GPi did not silence local neuronal activity uniformly, but instead loosely entrained firing and decreased net activity in a voltage-dependent fashion. Most neurons had decreased activity during stimulation, although some increased or did not change firing rate. Thirty-three of 45 neurons displayed complex patterns of entrainment during stimulation, and burst-firing was decreased consistently after stimulation. Recorded spike trains from patients were used as input into a model of a thalamocortical relay neuron. Only spike trains that occurred during therapeutically relevant voltages significantly reduced transmission error, an effect attributable to changes in firing patterns. These data indicate that DBS in the human GPi does not silence neuronal activity, but instead disrupts the pathological firing patterns through loose entrainment of neuronal activity.

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. The purpose of the present study was to fully characterize RVM ON- and OFF-cell responses to visual light by defining stimulus-response curves in male and female rats across a range of intensities (30 to 16,000 lx). We also determined if light-evoked responses are altered in animals subjected to persistent inflammation. We found that ON- and OFF-cells responded to relatively dim light (<1000 lx in naïve animals), with no difference between the sexes in threshold for light-evoked changes in firing or the percentage of responsive cells. Second, light-evoked suppression of OFF-cell firing was enhanced in persistent inflammation, with no change in light-evoked activation of ON-cells. These data indicate that pain-modulating neurons can be engaged by dim light, even under normal conditions. Further, they suggest that decreased descending inhibition during light exposure could contribute to reduced nociceptive thresholds in chronic pain states, resulting in light-induced somatic discomfort and aversion to light. Lastly, our findings argue for differences in how light and somatic stimuli engage RVM, and suggest that light-related input acts as a "top-down" regulatory input to RVM.

Pain-facilitating medullary neurons contribute to opioid-induced respiratory depression.

Respiratory depression is a therapy-limiting side effect of opioid analgesics, yet our understanding of the brain circuits mediating this potentially lethal outcome remains incomplete. Here we studied the contribution of the rostral ventromedial medulla (RVM), a region long implicated in pain modulation and homeostatic regulation, to opioid-induced respiratory depression. Microinjection of the µ-opioid agonist DAMGO in the RVM of lightly anesthetized rats produced both analgesia and respiratory depression, showing that neurons in this region can modulate breathing. Blocking opioid action in the RVM by microinjecting the opioid antagonist naltrexone reversed the analgesic and respiratory effects of systemically administered morphine, showing that this region plays a role in both the analgesic and respiratory-depressant properties of systemically administered morphine. The distribution of neurons directly inhibited by RVM opioid microinjection was determined with a fluorescent opioid peptide, dermorphin-Alexa 594, and found to be concentrated in and around the RVM. The non-opioid analgesic improgan, like DAMGO, produced antinociception but, unlike DAMGO, stimulated breathing when microinjected into the RVM. Concurrent recording of RVM neurons during improgan microinjection showed that this agent activated RVM ON-cells, OFF-cells, and NEUTRAL-cells. Since opioids are known to activate OFF-cells but suppress ON-cell firing, the differential respiratory response to these two analgesic drugs is best explained by their opposing effects on the activity of RVM ON-cells. These findings show that pain relief can be separated pharmacologically from respiratory depression and identify RVM OFF-cells as important central targets for continued development of potent analgesics with fewer side effects.

Shifting the Balance: How Top-Down and Bottom-Up Input Modulate Pain via 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. We quantified participants' visual photosensitivity thresholds (VPT) using an Ocular Photosensitivity Analyzer and measured pressure-pain sensitivity using pressure algometry. Participants also completed a battery of self-report measures related to chronic pain, TBI history, and mental health. A total of 395 participants completed testing, with 233 reporting a history of TBI. The TBI group was divided into 120 symptomatic TBI participants (s-TBI), and 113 asymptomatic TBI participants (a-TBI) based on their Neurobehavioral Symptom Inventory (NSI) scores. Participants in the s-TBI group scored significantly higher on self-reported chronic pain measures compared with a-TBI and no-TBI participants, including the Symptom Impact Questionnaire Revised (SIQR; p < 0.001) and the Michigan Body Map (MBM; p < 0.001). Despite differences in chronic pain complaints, groups displayed similar pressure-pain thresholds (p = 0.270). Additionally, s-TBI participants were more sensitive to light (lower VPT, p < 0.001), and VPT was correlated with SIQR scores across all participants (R = -0.452, p < 0.001). These data demonstrate that photosensitivity is associated with self-reported chronic pain and disability in individuals with chronic TBI symptomatology. Photosensitivity could therefore serve as a simple, more highly quantitative marker of high-impact chronic pain after TBI.

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. ON- and OFF-cells were identified within the RVM in females, with firing properties comparable to those described in males. In addition, both ON- and OFF-cells exhibited a sensitized response to somatic stimuli in females subjected to persistent inflammation, and both ON- and OFF-cells responded to systemically administered morphine at a dose sufficient to produce behavioral antinociception. These data demonstrate that the ON-/OFF-cell framework originally defined in males is also present in females, and that as in males, these neurons are recruited in females in persistent inflammation and by systemically administered morphine. Importantly, this work establishes a foundation for the use of female animals in studies of RVM and descending control.

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. Participants also completed validated questionnaires assessing chronic symptom severity in broad health-related domains (pain, sleep, quality of life, post-concussive symptoms). The HTEC was more sensitive (80% of participants in our cohort) than either self-report or EMR alone (40%). As expected from the high sensitivity, participants screening positive for TBI through the HTEC included many people with mild or no post-concussive symptoms. Participants were grouped according to degree of concordance across these diagnostic methods: no TBI, n = 43; or TBI-positive in any one method (TBI-1dx, n = 53), positive in any two (TBI-2dx, n = 45), or positive in all three (TBI-3dx, n = 59). The symptom profile of the TBI-1dx group was indistinguishable from the no TBI group. The TBI-3dx group had the most severe symptom profile. Our results show that understanding the exact methods used to ascertain TBI is essential when interpreting results from other studies, given that results and conclusions may differ dramatically depending on the method. This issue will become even more critical when interpreting data merged from multiple sources within newer, centralized repositories (e.g., Federal Interagency Traumatic Brain Injury Research [FITBIR]).

Deep brain stimulation does not silence neurons in subthalamic nucleus in Parkinson's patients.

Two broad hypotheses have been advanced to explain the clinical efficacy of deep brain stimulation (DBS) in the subthalamic nucleus (STN) for treatment of Parkinson's disease. One is that stimulation inactivates STN neurons, producing a functional lesion. The other is that electrical stimulation activates the STN output, thus "jamming" pathological activity in basal ganglia-corticothalamic circuits. Evidence consistent with both concepts has been adduced from modeling and animal studies, as well as from recordings in patients. However, the stimulation parameters used in many recording studies have not been well matched to those used clinically. In this study, we recorded STN activity in patients with Parkinson's disease during stimulation delivered through a clinical DBS electrode using standard therapeutic stimulus parameters. A microelectrode was used to record the firing of a single STN neuron during DBS (3-5 V, 80-200 Hz, 90- to 200-micros pulses; 33 neurons/11 patients). Firing rate was unchanged during the stimulus trains, and the recorded neurons did not show prolonged (s) changes in firing rate on termination of the stimulation. However, a brief (approximately 1 ms), short-latency (6 ms) postpulse inhibition was seen in 10 of 14 neurons analyzed. A subset of neurons displayed altered firing patterns, with a predominant shift toward random firing. These data do not support the idea that DBS inactivates the STN and are instead more consistent with the hypothesis that this stimulation provides a null signal to basal ganglia-corticothalamic circuitry that has been altered as part of Parkinson's disease.

Physiological basis for inhibition of morphine and improgan antinociception by CC12, a P450 epoxygenase inhibitor.

Many analgesic drugs, including µ-opioids, cannabinoids, and the novel nonopioid analgesic improgan, produce antinociception by actions in the rostral ventromedial medulla (RVM). There they activate pain-inhibiting neurons, termed "OFF-cells," defined by a nociceptive reflex-related pause in activity. Based on recent functional evidence that neuronal P450 epoxygenases are important for the central antinociceptive actions of morphine and improgan, we explored the convergence of opioid and nonopioid analgesic drug actions in RVM by studying the effects of the P450 epoxygenase inhibitor CC12 on the analgesic drug-induced activation of these OFF-cells and on behavioral antinociception. In rats lightly anesthetized with isoflurane, we recorded the effects of intraventricular morphine and improgan, with and without CC12 pretreatment, on tail flick latency and activity of identified RVM neurons: OFF-cells, ON-cells (pronociceptive neurons), and neutral cells (unresponsive to analgesic drugs). CC12 pretreatment preserved reflex-related changes in OFF-cell firing and blocked the analgesic actions of both drugs, without interfering with the increase in spontaneous firing induced by improgan or morphine. CC12 blocked suppression of evoked ON-cell firing by improgan, but not morphine. CC12 pretreatment had no effect by itself on RVM neurons or behavior. These data show that the epoxygenase inhibitor CC12 works downstream from receptors for both µ-opioid and improgan, at the inhibitory input mediating the OFF-cell pause. This circuit-level analysis thus provides a cellular basis for the convergence of opioid and nonopioid analgesic actions in the RVM. A presynaptic P450 epoxygenase may therefore be an important target for development of clinically useful nonopioid analgesic drugs.

Medullary pain facilitating neurons mediate allodynia in headache-related pain.

OBJECTIVE: To develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches. To explore neural mechanisms underlying cephalic and extracephalic allodynia. METHODS: Inflammatory mediators (IM) were applied to the dura of unanesthetized rats via previously implanted cannulas, and sensory thresholds of the face and hind-paws were characterized. RESULTS: IM elicited robust facial and hind-paw allodynia, which peaked within 3 hours. These effects were reminiscent of cutaneous allodynia seen in patients with migraine or other primary headache conditions, and were reversed by agents used clinically in the treatment of migraine, including sumatriptan, naproxen, and a calcitonin gene-related peptide antagonist. Consistent with clinical observations, the allodynia was unaffected by a neurokinin-1 antagonist. Having established facial and hind-paw allodynia as a useful animal surrogate of headache-associated allodynia, we next showed that blocking pain-facilitating processes in the rostral ventromedial medulla (RVM) interfered with its expression. Bupivacaine, destruction of putative pain-facilitating neurons, or block of cholecystokinin receptors prevented or significantly attenuated IM-induced allodynia. Electrophysiological studies confirmed activation of pain-facilitating RVM "on" cells and transient suppression of RVM "off" cells after IM. INTERPRETATION: Facial and hind-paw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for development of novel therapeutic strategies for headache pain. The data also demonstrate the requirement for activation of descending facilitation from the RVM for the expression of cranial and extracranial cutaneous allodynia, and are consistent with a brainstem generator of allodynia associated with headache disorders.

Sensitization of pain-modulating neurons in the rostral ventromedial medulla after peripheral nerve injury.

Nerve injury can lead to mechanical hypersensitivity in both humans and animal models, such that innocuous touch produces pain. Recent functional studies have demonstrated a critical role for descending pain-facilitating influences from the rostral ventromedial medulla (RVM) in neuropathic pain, but the underlying mechanisms and properties of the relevant neurons within the RVM are essentially unknown. We therefore characterized mechanical responsiveness of physiologically characterized neurons in the RVM after spinal nerve ligation, a model of neuropathic pain that produces robust mechanical hyperalgesia and allodynia. RVM neurons were studied 7-14 d after spinal nerve ligation, and classified as "on-cells," "off-cells," or "neutral cells" using standard criteria of changes in firing associated with heat-evoked reflexes. On-cells are known to promote nociception, and off-cells to suppress nociception, whereas the role of neutral cells in pain modulation remains an open question. Neuronal and behavioral responses to innocuous and noxious mechanical stimulation were tested using calibrated von Frey filaments (4-100 g) applied to the hindpaws ipsilateral and contralateral to the injury, and in sham-operated and unoperated control animals. On- and off-cells recorded in nerve-injured animals exhibited novel responses to innocuous mechanical stimulation, and enhanced responses to noxious mechanical stimulation. Neuronal hypersensitivity in the RVM was correlated with behavioral hypersensitivity. Neutral cells remained unresponsive to cutaneous stimulation after nerve injury. These data demonstrate that both on- and off-cells in the RVM are sensitized to innocuous and noxious mechanical stimuli after nerve injury. This sensitization likely contributes to allodynia and hyperalgesia of neuropathic pain states.