Dynamic causal modeling reveals increased cerebellar- periaqueductal gray communication during fear extinction.

Introduction: The extinction of fear memories is an important component in regulating defensive behaviors, contributing toward adaptive processes essential for survival. The cerebellar medial nucleus (MCN) has bidirectional connections with the ventrolateral periaqueductal gray (vlPAG) and is implicated in the regulation of multiple aspects of fear, such as conditioned fear learning and the expression of defensive motor outputs. However, it is unclear how communication between the MCN and vlPAG changes during conditioned fear extinction. Methods: We use dynamic causal models (DCMs) to infer effective connectivity between the MCN and vlPAG during auditory cue-conditioned fear retrieval and extinction in the rat. DCMs determine causal relationships between neuronal sources by using neurobiologically motivated models to reproduce the dynamics of post-synaptic potentials generated by synaptic connections within and between brain regions. Auditory event related potentials (ERPs) during the conditioned tone offset were recorded simultaneously from MCN and vlPAG and then modeled to identify changes in the strength of the synaptic inputs between these brain areas and the relationship to freezing behavior across extinction trials. The DCMs were structured to model evoked responses to best represent conditioned tone offset ERPs and were adapted to represent PAG and cerebellar circuitry. Results: With the use of Parametric Empirical Bayesian (PEB) analysis we found that the strength of the information flow, mediated through enhanced synaptic efficacy from MCN to vlPAG was inversely related to freezing during extinction, i.e., communication from MCN to vlPAG increased with extinction. Discussion: The results are consistent with the cerebellum contributing to predictive processes that underpin fear extinction.

When Differential Descending Control of Speed Matters: Descending Modulation of A- versus C-Fiber Evoked Spinal Nociception.

Descending pain modulatory systems (DPMS) that originate within the brain and act to modulate spinal nociceptive transmission are a major determinant of the acute and chronic pain experience. Investigations of these systems in basic scientific research is critical to the development of therapeutic strategies for the relief of pain. Despite our best efforts, something is lost in translation. This article will explore whether this is due in part to a primary focus on sensory modality leading to a failure to differentiate between descending control of A- vs. C-fiber mediated spinal nociception.

Cerebellar modulation of memory encoding in the periaqueductal grey and fear behaviour.

The pivotal role of the periaqueductal grey (PAG) in fear learning is reinforced by the identification of neurons in male rat ventrolateral PAG (vlPAG) that encode fear memory through signalling the onset and offset of an auditory-conditioned stimulus during presentation of the unreinforced conditioned tone (CS+) during retrieval. Some units only display CS+ onset or offset responses, and the two signals differ in extinction sensitivity, suggesting that they are independent of each other. In addition, understanding cerebellar contributions to survival circuits is advanced by the discovery that (i) reversible inactivation of the medial cerebellar nucleus (MCN) during fear consolidation leads in subsequent retrieval to (a) disruption of the temporal precision of vlPAG offset, but not onset responses to CS+, and (b) an increase in duration of freezing behaviour. And (ii) chemogenetic manipulation of the MCN-vlPAG projection during fear acquisition (a) reduces the occurrence of fear-related ultrasonic vocalisations, and (b) during subsequent retrieval, slows the extinction rate of fear-related freezing. These findings show that the cerebellum is part of the survival network that regulates fear memory processes at multiple timescales and in multiple ways, raising the possibility that dysfunctional interactions in the cerebellar-survival network may underlie fear-related disorders and comorbidities.

Anxiety disorders are a cluster of mental health conditions characterised by persistent and excessive amounts of fear and worry. They affect millions of people worldwide, but treatments can sometimes be ineffective and have unwanted side effects. Understanding which brain regions are involved in fear and anxiety-related behaviours, and how those areas are connected, is the first step towards designing more effective treatments. A region known as the periaqueductal grey (or PAG) sits at the centre of the brain's fear and anxiety network, regulating pain, encoding fear memories and responding to threats and stressors. It also controls survival behaviours such as the 'freeze' response, when an animal is frightened. A more recent addition to the fear and anxiety network is the cerebellum, which sits at the base of the brain. Two-way connections between this region and the PAG have been well described, but how the cerebellum might influence fear and anxiety-related behaviours remains unclear. To explore this role, Lawrenson, Paci et al. investigated whether the cerebellum modulates brain activity within the PAG and if so, how this relates to fear behaviours. Rats had electrodes implanted in their brains to record the activity of nerve cells within the PAG. A common fear-conditioning task was then used to elicit 'freeze' responses: a sound was paired with mild foot shocks until the animals learned to fear the auditory signal. In the rats, a subset of neurons within the PAG responded to the tone, consistent with those cells encoding a fear memory. But when a drug blocked the cerebellum's output during fear conditioning, the timing of the PAG response was less precise and the rats' freeze response lasted longer. Lawrenson, Paci et al. concluded that the cerebellum, through its interactions with the brain's fear and anxiety network, might be responsible for coordinating the most appropriate behavioural response to fear, and how long 'freezing' lasts. In summary, these findings show that the cerebellum is a part of the brain's survival network which regulates fear-memory processes. It raises the possibility that disruption of the cerebellum might underlie anxiety and other fear-related disorders, thereby providing a new target for future therapies.

Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats.

The loss of descending inhibitory control is thought critical to the development of chronic pain but what causes this loss in function is not well understood. We have investigated the dynamic contribution of prelimbic cortical neuronal projections to the periaqueductal grey (PrL-P) to the development of neuropathic pain in rats using combined opto- and chemogenetic approaches. We found PrL-P neurons to exert a tonic inhibitory control on thermal withdrawal thresholds in uninjured animals. Following nerve injury, ongoing activity in PrL-P neurons masked latent hypersensitivity and improved affective state. However, this function is lost as the development of sensory hypersensitivity emerges. Despite this loss of tonic control, opto-activation of PrL-P neurons at late post-injury timepoints could restore the anti-allodynic effects by inhibition of spinal nociceptive processing. We suggest that the loss of cortical drive to the descending pain modulatory system underpins the expression of neuropathic sensitisation after nerve injury.

The partial saphenous nerve injury model of pain impairs reward-related learning but not reward sensitivity or motivation.

ABSTRACT: Chronic pain is highly comorbid with affective disorders, including major depressive disorder. A core feature of major depressive disorder is a loss of interest in previously rewarding activities. Major depressive disorder is also associated with negative affective biases where cognitive processes are modulated by the affective state. Previous work from our laboratory has shown that reward-related learning and memory is impaired in rodent models of depression generated through a variety of different manipulations. This study investigated different aspects of reward-related behaviour in a rodent model of chronic pain, the partial saphenous nerve injury (PSNI). Using our reward-learning assay, an impairment in reward learning was observed with no difference in sucrose preference, consistent with a lack of effect on reward sensitivity and similar to the effects seen in depression models. In a successive negative contrast task, chronic pain was not associated with changes in motivation for reward either under normal conditions or when reward was devalued although both sham and PSNI groups exhibited the expected negative contrast effect. In the affective bias test, PSNI rats developed a positive affective bias when treated with gabapentin, an effect not seen in the controls suggesting an association with the antinociceptive effects of the drug inducing a relatively more positive affective state. Together, these data suggest that there are changes in reward-related cognition in this chronic pain model consistent with previous findings in rodent models of depression. The effects seen with gabapentin suggest that pain-associated negative affective state may be remediated by this atypical analgesic.

Repeated exposure of naïve and peripheral nerve-injured mice to a snake as an experimental model of post-traumatic stress disorder and its co-morbidity with neuropathic pain.

Confrontation of rodents by natural predators provides a number of advantages as a model for traumatic or stressful experience. Using this approach, one of the aims of this study was to investigate a model for the study of post-traumatic stress disorder (PTSD)-related behaviour in mice. Moreover, because PTSD can facilitate the establishment of chronic pain (CP), and in the same way, patients with CP have an increased tendency to develop PTSD when exposed to a traumatic event, our second aim was to analyse whether this comorbidity can be verified in the new paradigm. C57BL/6 male mice underwent chronic constriction injury of the sciatic nerve (CCI), a model of neuropathic CP, or not (sham groups) and were submitted to different threatening situations. Threatened mice exhibited enhanced defensive behaviours, as well as significantly enhanced risk assessment and escape behaviours during context reexposure. Previous snake exposure reduced open-arm time in the elevated plus-maze test, suggesting an increase in anxiety levels. Sham mice showed fear-induced antinociception immediately after a second exposure to the snake, but 1 week later, they exhibited allodynia, suggesting that multiple exposures to the snake led to increased nociceptive responses. Moreover, after reexposure to the aversive environment, allodynia was maintained. CCI alone produced intense allodynia, which was unaltered by exposure to either the snake stimuli or reexposure to the experimental context. Together, these results specifically parallel the behavioural symptoms of PTSD, suggesting that the snake/exuvia/reexposure procedure may constitute a useful animal model to study PTSD.

Correction to: Cerebellar Modules and Their Role as Operational Cerebellar Processing Units: A Consensus paper.

In the original version of this paper, the Title should have been written with "A Consensus paper" to read "Cerebellar Modules and Their Role as Operational Cerebellar Processing Units: A Consensus paper".

Cerebellar Modules and Their Role as Operational Cerebellar Processing Units: A Consensus paper [corrected].

The compartmentalization of the cerebellum into modules is often used to discuss its function. What, exactly, can be considered a module, how do they operate, can they be subdivided and do they act individually or in concert are only some of the key questions discussed in this consensus paper. Experts studying cerebellar compartmentalization give their insights on the structure and function of cerebellar modules, with the aim of providing an up-to-date review of the extensive literature on this subject. Starting with an historical perspective indicating that the basis of the modular organization is formed by matching olivocorticonuclear connectivity, this is followed by consideration of anatomical and chemical modular boundaries, revealing a relation between anatomical, chemical, and physiological borders. In addition, the question is asked what the smallest operational unit of the cerebellum might be. Furthermore, it has become clear that chemical diversity of Purkinje cells also results in diversity of information processing between cerebellar modules. An additional important consideration is the relation between modular compartmentalization and the organization of the mossy fiber system, resulting in the concept of modular plasticity. Finally, examination of cerebellar output patterns suggesting cooperation between modules and recent work on modular aspects of emotional behavior are discussed. Despite the general consensus that the cerebellum has a modular organization, many questions remain. The authors hope that this joint review will inspire future cerebellar research so that we are better able to understand how this brain structure makes its vital contribution to behavior in its most general form.

The mystery of the cerebellum: clues from experimental and clinical observations.

The cerebellum has a striking homogeneous cytoarchitecture and participates in both motor and non-motor domains. Indeed, a wealth of evidence from neuroanatomical, electrophysiological, neuroimaging and clinical studies has substantially modified our traditional view on the cerebellum as a sole calibrator of sensorimotor functions. Despite the major advances of the last four decades of cerebellar research, outstanding questions remain regarding the mechanisms and functions of the cerebellar circuitry. We discuss major clues from both experimental and clinical studies, with a focus on rodent models in fear behaviour, on the role of the cerebellum in motor control, on cerebellar contributions to timing and our appraisal of the pathogenesis of cerebellar tremor. The cerebellum occupies a central position to optimize behaviour, motor control, timing procedures and to prevent body oscillations. More than ever, the cerebellum is now considered as a major actor on the scene of disorders affecting the CNS, extending from motor disorders to cognitive and affective disorders. However, the respective roles of the mossy fibres, the climbing fibres, cerebellar cortex and cerebellar nuclei remains unknown or partially known at best in most cases. Research is now moving towards a better definition of the roles of cerebellar modules and microzones. This will impact on the management of cerebellar disorders.

Top down control of spinal sensorimotor circuits essential for survival.

The ability to interact with challenging environments requires coordination of sensory and motor systems that underpin appropriate survival behaviours. All animals, including humans, use active and passive coping strategies to react to escapable or inescapable threats, respectively. Across species the neural pathways involved in survival behaviours are highly conserved and there is a consensus that knowledge of such pathways is a fundamental step towards understanding the neural circuits underpinning emotion in humans and treating anxiety or other prevalent emotional disorders. The midbrain periaqueductal grey (PAG) lies at the heart of the defence-arousal system and its integrity is paramount to the expression of survival behaviours. To date, studies of 'top down control' components of defence behaviours have focused largely on the sensory and autonomic consequences of PAG activation. In this context, effects on motor activity have received comparatively little attention, despite overwhelming evidence of a pivotal role for the PAG in coordinating motor responses essential to survival (e.g. such as freezing in response to fear). In this article we provide an overview of top down control of sensory functions from the PAG, including selective control of different modalities of sensory, including proprioceptive, information forwarded to a major supsraspinal motor control centre, the cerebellum. Next, evidence from our own and other laboratories of PAG control of motor outflow is also discussed. Finally, the integration of sensorimotor functions by the PAG is considered, as part of coordinated defence behaviours that prepare an animal to be ready and able to react to danger.

Neural Correlates of Fear in the Periaqueductal Gray.

The dorsal and ventral periaqueductal gray (dPAG and vPAG, respectively) are embedded in distinct survival networks that coordinate, respectively, innate and conditioned fear-evoked freezing. However, the information encoded by the PAG during these survival behaviors is poorly understood. Recordings in the dPAG and vPAG in rats revealed differences in neuronal activity associated with the two behaviors. During innate fear, neuronal responses were significantly greater in the dPAG compared with the vPAG. After associative fear conditioning and during early extinction (EE), when freezing was maximal, a field potential was evoked in the PAG by the auditory fear conditioned stimulus (CS). With repeated presentations of the unreinforced CS, animals displayed progressively less freezing accompanied by a reduction in event-related field potential amplitude. During EE, the majority of dPAG and vPAG units increased their firing frequency, but spike-triggered averaging showed that only ventral activity during the presentation of the CS was significantly coupled to EMG-related freezing behavior. This PAG-EMG coupling was only present for the onset of freezing activity during the CS in EE. During late extinction, a subpopulation of units in the dPAG and vPAG continued to show CS-evoked responses; that is, they were extinction resistant. Overall, these findings support roles for the dPAG in innate and conditioned fear and for the vPAG in initiating but not maintaining the drive to muscles to generate conditioned freezing. The existence of extinction-susceptible and extinction-resistant cells also suggests that the PAG plays a role in encoding fear memories. SIGNIFICANCE STATEMENT: The periaqueductal gray (PAG) orchestrates survival behaviors, with the dorsal (dPAG) and ventral (vPAG) PAG concerned respectively with innate and learnt fear responses. We recorded neural activity from dPAG and vPAG in rats during the expression of innate fear and extinction of learned freezing. Cells in dPAG responded more robustly during innate fear, but dPAG and vPAG both encoded the time of the conditioned stimulus during early extinction and displayed extinction sensitive and resistant characteristics. Only vPAG discharge was correlated with muscle activity, but this was limited to the onset of conditioned freezing. The data suggest that the roles of dPAG and vPAG in fear behavior are more complex than previously thought, including a potential role in fear memory.

Does inflammation induced by ultraviolet B and heat rekindling alter pain-related behaviour in rats?

OBJECTIVE: To investigate whether induction of the ultraviolet B and heat rekindling (UVB/HR) model alters burrowing behaviour in rats. STUDY DESIGN: Randomized, blinded, prospective experimental study. ANIMALS: Sixteen adult male Wistar rats weighing 250-300 g. METHODS: In the UVB/HR group (n = 8), UV irradiation was delivered to the heel area of the right plantar pelvic limb paw at a dose of 1000 mJ cm(-2) , using a narrow-band UVB light source. Twenty-four hours later, heat rekindling was performed by placement of a feedback-controlled thermode set at a constant temperature of 45 °C over the area of UVB irradiation for 5 minutes. Both interventions were carried out under pentobarbital anaesthesia. The 'sham' group (n = 8) was anaesthetized only. In the burrowing test, rats were housed singly for 2 hours in cages furnished with a burrow filled with sand. The amount of sand remaining in the burrow after 2 hours was weighed and the amount displaced from the burrow calculated. The burrowing test was carried out for two consecutive days prior to UVB irradiation (day 0), on day 1 prior to HR, on days 2 and 3 after UVB exposure and at equivalent time points in the sham group. RESULTS: Rats in the sham group burrowed means (SD) of 2429 (73) g and 2358 (124) g of sand on days -2 and 3, respectively, while those in the UVB/HR group burrowed 2460 (26) and 2419 (58) g on days -2 and 3, respectively. There was no significant effect of treatment on the amount of sand burrowed at any time point. CONCLUSIONS AND CLINICAL RELEVANCE: Pain associated with UVB/HR model induction is below the threshold required to affect rat burrowing behaviour and therefore questions the face validity of UVB/HR as a translational model of inflammatory pain.

The Periaqueductal Gray Orchestrates Sensory and Motor Circuits at Multiple Levels of the Neuraxis.

The periaqueductal gray (PAG) coordinates behaviors essential to survival, including striking changes in movement and posture (e.g., escape behaviors in response to noxious stimuli vs freezing in response to fear-evoking stimuli). However, the neural circuits underlying the expression of these behaviors remain poorly understood. We demonstrate in vivo in rats that activation of the ventrolateral PAG (vlPAG) affects motor systems at multiple levels of the neuraxis through the following: (1) differential control of spinal neurons that forward sensory information to the cerebellum via spino-olivo-cerebellar pathways (nociceptive signals are reduced while proprioceptive signals are enhanced); (2) alterations in cerebellar nuclear output as revealed by changes in expression of Fos-like immunoreactivity; and (3) regulation of spinal reflex circuits, as shown by an increase in α-motoneuron excitability. The capacity to coordinate sensory and motor functions is demonstrated in awake, behaving rats, in which natural activation of the vlPAG in fear-conditioned animals reduced transmission in spino-olivo-cerebellar pathways during periods of freezing that were associated with increased muscle tone and thus motor outflow. The increase in spinal motor reflex excitability and reduction in transmission of ascending sensory signals via spino-olivo-cerebellar pathways occurred simultaneously. We suggest that the interactions revealed in the present study between the vlPAG and sensorimotor circuits could form the neural substrate for survival behaviors associated with vlPAG activation. SIGNIFICANCE STATEMENT: Neural circuits that coordinate survival behaviors remain poorly understood. We demonstrate in rats that the periaqueductal gray (PAG) affects motor systems at the following multiple levels of the neuraxis: (1) through altering transmission in spino-olivary pathways that forward sensory signals to the cerebellum, reducing and enhancing transmission of nociceptive and proprioceptive information, respectively; (2) by alterations in cerebellar output; and (3) through enhancement of spinal motor reflex pathways. The sensory and motor effects occurred at the same time and were present in both anesthetized animals and behavioral experiments in which fear conditioning naturally activated the PAG. The results provide insights into the neural circuits that enable an animal to be ready and able to react to danger, thus assisting in survival.

Beyond Gene Inactivation: Evolution of Tools for Analysis of Serotonergic Circuitry.

In the brain, serotonin (5-hydroxytryptamine, 5-HT) controls a multitude of physiological and behavioral functions. Serotonergic neurons in the raphe nuclei give rise to a complex and extensive network of axonal projections throughout the whole brain. A major challenge in the analysis of these circuits is to understand how the serotonergic networks are linked to the numerous functions of this neurotransmitter. In the past, many studies employed approaches to inactivate different genes involved in serotonergic neuron formation, 5-HT transmission, or 5-HT metabolism. Although these approaches have contributed significantly to our understanding of serotonergic circuits, they usually result in life-long gene inactivation. As a consequence, compensatory changes in serotonergic and other neurotransmitter systems may occur and complicate the interpretation of the observed phenotypes. To dissect the complexity of the serotonergic system with greater precision, approaches to reversibly manipulate subpopulations of serotonergic neurons are required. In this review, we summarize findings on genetic animal models that enable control of 5-HT neuronal activity or mapping of the serotonergic system. This includes a comparative analysis of several mouse and rat lines expressing Cre or Flp recombinases under Tph2, Sert, or Pet1 promoters with a focus on specificity and recombination efficiency. We further introduce applications for Cre-mediated cell-type specific gene expression to optimize spatial and temporal precision for the manipulation of serotonergic neurons. Finally, we discuss other temporally regulated systems, such as optogenetics and designer receptors exclusively activated by designer drugs (DREADD) approaches to control 5-HT neuron activity.

Differential contributions of A- and C-nociceptors to primary and secondary inflammatory hypersensitivity in the rat.

Primary hyperalgesia is characterized by increased responsiveness to both heat and mechanical stimulation in the area of injury. By contrast, secondary hyperalgesia is generally associated with increased responses to mechanical but not heat stimuli. We tested the hypothesis that sensitization in secondary hyperalgesia is dependent on the class of peripheral nociceptor (C- or A-nociceptor) rather than the modality of stimulation (mechanical vs heat). A- and C-nociceptors were selectively activated using contact heat ramps applied to the hind paw dorsum in animals with hind paw inflammation (primary hyperalgesia) and knee inflammatory arthritis (secondary hyperalgesia). Sensitization to A- and C-nociceptor activation in primary and secondary hyperalgesia was assessed by reflex withdrawal thresholds and by Fos immunocytochemistry in the dorsal horn of the spinal cord, as an index of neuronal activation. In primary hyperalgesia, only C-nociceptor-evoked withdrawal reflexes were sensitized. This was associated with increased spinal lamina I neuronal activation to both A- and C-nociceptor activation. Fos-like immunoreactivity (FLI) was unchanged in other dorsal horn laminae. In secondary hyperalgesia, only A-nociceptor-evoked withdrawal reflexes were sensitized, and FLI was increased in both superficial and deep dorsal laminae. Neurons in the superficial dorsal horn receive and process nociceptor inputs from the area of primary hyperalgesia, resulting in functional sensitization to C-nociceptive inputs. In inflammatory arthritis, secondary hyperalgesia is evoked by A-nociceptor thermal stimulation, suggesting that secondary hyperalgesia is A-nociceptor, rather than stimulus modality (mechanical vs thermal), dependent. Fos-like immunoreactivity evoked by A-nociceptor stimulation in secondary hyperalgesia suggests that the sensitization is underpinned by spinal neuronal sensitization in laminae I and IV/V.

Intrathecal reboxetine suppresses evoked and ongoing neuropathic pain behaviours by restoring spinal noradrenergic inhibitory tone.

The descending noradrenergic (NAergic) projection to the spinal cord forms part of an endogenous analgesic system. After nerve injury, a localised failure in this compensatory system has been implicated as a permissive factor in the development of neuropathic sensitisation. We investigated whether restoring descending NAergic tone with intrathecal reboxetine can oppose the development of the neuropathic pain phenotype after tibial nerve transection (TNT). Rats had a lumbar intrathecal catheter implanted at the time of nerve injury for administration of reboxetine (10 µg) in both acute and chronic dosing experiments. In acute dosing experiments, both intrathecal and systemic (30 mg/kg) reboxetine partially reversed mechanical allodynia. This antiallodynic effect of intrathecal reboxetine was blocked by prior administration of yohimbine (α2-adrenoceptor antagonist, 30 µg) but not by prazosin (α1-adrenoceptor antagonist, 30 µg) or propranolol (ß-adrenoceptor antagonist, 100 µg). Chronic intrathecal reboxetine (10 µg, intrathecally, twice daily for 2 weeks) suppressed the development of cold and mechanical allodynia. Nerve-injured animals demonstrated a place preference for intrathecal reboxetine, suggesting that it also reduced spontaneous pain. In contrast, an equivalent antiallodynic dose of systemic reboxetine (30 mg/kg) was aversive in both naive and TNT rats. On cessation of chronic intrathecal reboxetine, there was a gradual development of allodynic sensitisation that was indistinguishable from control TNT animals by 7 days after the end of dosing. Our results suggest that pharmacological restoration of spinal NAergic tone with intrathecal reboxetine can suppress both allodynia and spontaneous pain in the TNT model.

Periaqueductal grey cyclooxygenase-dependent facilitation of C-nociceptive drive and encoding in dorsal horn neurons in the rat.

The experience of pain is strongly affected by descending control systems originating in the brainstem ventrolateral periaqueductal grey (VL-PAG), which control the spinal processing of nociceptive information. A- and C-fibre nociceptors detect noxious stimulation, and have distinct and independent contributions to both the perception of pain quality (fast and slow pain, respectively) and the development of chronic pain. Evidence suggests a separation in the central processing of information arising from A- vs. C-nociceptors; for example, inhibition of the cyclooxygenase-1 (COX-1)-prostaglandin system within the VL-PAG alters spinal nociceptive reflexes evoked by C-nociceptor input in vivo via descending pathways, leaving A-nociceptor-evoked reflexes largely unaffected. As the spinal neuronal mechanisms underlying these different responses remain unknown, we determined the effect of inhibition of VL-PAG COX-1 on dorsal horn wide dynamic-range neurons evoked by C- vs. A-nociceptor activation. Inhibition of VL-PAG COX-1 in anaesthetised rats increased firing thresholds of lamina IV-V wide dynamic-range dorsal horn neurons in response to both A- and C-nociceptor stimulation. Importantly, wide dynamic-range dorsal horn neurons continued to faithfully encode A-nociceptive information, even after VL-PAG COX-1 inhibition, whereas the encoding of C-nociceptor information by wide dynamic-range spinal neurons was significantly disrupted. Dorsal horn neurons with stronger C-nociceptor input were affected by COX-1 inhibition to a greater extent than those with weak C-fibre input. These data show that the gain and contrast of C-nociceptive information processed in individual wide dynamic-range dorsal horn neurons is modulated by prostanergic descending control mechanisms in the VL-PAG.