Armando Almeida

Neuropathic pain is associated with depressive behaviour and induces neuroplasticity in the amygdala of the rat

Chronic pain is associated with the development of affective disorders but the underlying mechanisms are not fully understood. Changes in brain centres implicated in both emotional and pain processing are likely to be critical in the interplay of pain control and affective emotional behaviour. In the present study, we assessed emotional behaviour and performed a structural analysis of the amygdala (AMY) in neuropathic rats after two months of hyperalgesia and allodynia, induced by the spared nerve injury model (SNI). When compared with Sham-controls, SNI animals displayed signs of depressive-like behaviour. In addition, we found an increased amygdalar volume in SNI rats. No alterations were found in the dendritic arborizations of AMY neurons but, surprisingly, the amygdalar hypertrophy was associated with an increased cell proliferation [bromodeoxyuridine (BrdU)-positive cells] in the central (CeA) and basolateral (BLA) amygdaloid nuclei. The phenotypic analysis of the newly-acquired cells revealed that they co-label for neuronal markers (BrdU+NeuN and BrdU+Calbindin), but not for differentiated glial cells (BrdU+glial fibrillary acidic protein). We demonstrate that neuropathic pain promotes generation of new neurons in the AMY. Given the established role of the AMY in emotional behaviour, we propose that these neuroplastic changes might contribute for the development of depressive-like symptoms that are usually present in prolonged pain syndromes in humans.

The medullary dorsal reticular nucleus as a pronociceptive centre of the pain control system.

The endogenous pain control system has long been considered as engaged in pain depression through the commitment of multiple descending actions that reduce the response capacity of spinal dorsal horn nociceptive neurones. Such a pure inhibitory antinociceptive nature was lately questioned by the observation of pronociceptive effects from areas classically regarded as antinociceptive. The thereby raised hypothesis of a more versatile functional arrangement that dynamically adjusts the pain modulatory effect to multiple conditions by balancing several excitatory and inhibitory actions found strong support on the recent discovery of a medullary area particularly dedicated to pain facilitation. Lesioning the medullary dorsal reticular nucleus (DRt) depresses nociceptive responses to acute and inflammatory pain, whereas stimulation produces the inverse effect. The decrease in formalin-induced pain behaviour following DRt lesioning is accompanied by a decrease of spinal noxious-evoked c-fos neuronal activation. DRt blocking by lidocaine results in a decrease of the nociceptive activity of spinal dorsal horn neurones, whereas stimulation by glutamate has the opposite effect. A reciprocal disynaptic putative excitatory circuit that links the DRt and the spinal dorsal horn and conveys nociceptive input through the ascending branch was described, indicating that the DRt pain facilitating action is mediated by a reverberating spino-DRt circuit that promotes the enhancement of the response capacity of spinal neurones to noxious stimulation.The demonstration of a primary pronociceptive centre in the endogenous pain control system brings new important data to the emerging concept of pain modulation as a dynamic and flexible process that integrates nociceptive processing by balancing multiple excitatory and inhibitory actions as the way of adapting to the various unsteady pain determinants.

The impact of age on emotional and cognitive behaviours triggered by experimental neuropathy in rats

ABSTRACT Chronic pain syndromes encompass several clinical entities that frequently affect the individuals’ emotional and cognitive behaviours which, in turn, can also alter pain perception. Additionally, both pain perception and motivational‐affective behaviours change with increasing age. In order to evaluate the influence of age upon the interaction between chronic pain and affective/cognitive behaviours, 3‐, 10‐ and 22‐month‐old rats with 1 month neuropathy (spared nerve injury, SNI model) were compared with age‐matched sham‐operated controls in the open field (OF; locomotor and exploratory behaviours), elevated plus‐maze (EPM; anxiety‐like behaviour), forced swimming (FST; depressive‐like behaviour), working memory water maze (WM; spatial short‐term memory), Morris water maze (MWM; spatial reference memory) and spatial reversal (behavioural flexibility) tests. Locomotor and exploratory activities decreased steadily with age and were further reduced by SNI. Aging was associated with increased anxiety‐like behaviour, which was potentiated by SNI in both 3‐ and 22‐month‐old rats. The performance in the FST was affected by SNI but only in mid‐aged animals. Cognitive performances in the MWM and spatial reversal tests deteriorated with age; however, the SNI lesion was only detrimental in the reversal task to mid‐aged animals. Our data demonstrate that the influence of neuropathic pain on affective and cognitive behaviours is age dependent and varies with the behavioural domain that is tested. Importantly, mid‐aged animals seem to be more susceptible to depression and cognitive deterioration associated to chronic pain than young and old groups.

The medullary dorsal reticular nucleus facilitates acute nociception in the rat

The influence on pain processing caused by destruction or stimulation of the dorsal reticular nucleus (DRt) was studied using the tail-flick and the increasing temperature hot-plate tests. Lesions of the DRt were obtained by injecting quinolinic acid (180 nmol/microliters) unilaterally or bilaterally, and nociceptive responses were evaluated by both tests. Following unilateral lesions, the tail-flick latencies and the hot-plate response temperatures were increased, values differing statistically from controls in the latter test. Bilateral lesions resulted in statistically significant increases of both tail-flick latency and hot-plate response temperature. Stimulation of the DRt was performed by injecting glutamate (100 nmol/microliters) unilaterally, which was followed 1 min later by a significant decrease in the tail-flick latency compared to saline injected controls. These results suggest that the DRt is involved in the facilitation of nociception after acute thermal noxious stimulation. This effect may be mediated through a spino-DRt-spinal loop causing a rebound of excitation in lamina I cells receiving noxious input from their own receptive field.

The mediating role of pain catastrophizing in the relationship between presurgical anxiety and acute postsurgical pain after hysterectomy

Summary This is the first study showing that it is not presurgical anxiety per se that predicts postsurgical pain intensity, but rather anxiety fully mediated through pain catastrophizing. ABSTRACT The aim of this study was to examine the joint role of demographic, clinical, and psychological variables as predictors of acute postsurgical pain in women undergoing hysterectomy due to benign disorders. A consecutive sample of 203 women was assessed 24 hours before (T1) and 48 hours after (T2) surgery. Baseline pain and predictors were assessed at T1 and postsurgical pain and analgesic consumption at T2. Several factors distinguished women who had no or mild pain after surgery from those who had moderate to severe pain, with the latter being younger, having more presurgical pain, and showing a less favorable psychological profile. Younger age (odds ratio [OR] = 0.90, P < .001), presurgical pain (OR = 2.50, P <.05), pain due to other causes (OR = 4.39, P = .001), and pain catastrophizing (OR = 3.37, P = .001) emerged as the main predictors of pain severity at T2 in multivariate logistic regression. This was confirmed in hierarchical linear regression (β = −0.187, P < .05; β = 0.146, P < .05; β = 0.136, P < .05; β = 0.245, P < .01, respectively). Presurgical anxiety also predicted pain intensity at T2. Findings revealed an integrative heuristic model that accounts for the joint influence of demographic, clinical, and psychological factors on postsurgical pain intensity and severity. In further mediation analysis, pain catastrophizing emerged as a full mediator between presurgical anxiety and postsurgical pain intensity. The potential clinical implications for understanding, evaluating, and intervening in postsurgical pain are discussed.

Predictors of acute postsurgical pain and anxiety following primary total hip and knee arthroplasty.

UNLABELLED This study aims to examine the joint role of demographic, clinical, and psychological variables as predictors of acute postsurgical pain and anxiety in patients undergoing total knee arthroplasty and total hip arthroplasty. A consecutive sample of 124 patients was assessed 24 hours before (T1) and 48 hours after (T2) surgery. Demographic, clinical, and psychological factors were assessed at T1 and several postsurgical pain issues, anxiety, and analgesic consumption were evaluated at T2. Hierarchical linear regression analyses were performed to identify predictors of acute pain and anxiety following surgery. In the final multivariate model, presurgical optimism emerged as the main significant predictor of postsurgical pain intensity. Presurgical optimism also had a significant role in the prediction of postsurgical anxiety, together with presurgical anxiety level and emotional representation of the condition leading to surgery (osteoarthritis). A significant positive correlation between postsurgical anxiety and acute pain was also confirmed. The present study enhances our understanding of predictors of acute pain and anxiety following total knee arthroplasty and total hip arthroplasty by showing the relevance of psychological factors, over and above other potential clinical predictors. These findings could be used to develop targeted interventions aimed at acute postsurgical pain and anxiety management following major joint arthroplasties. PERSPECTIVE This article reveals the significant influence of psychological factors on the prediction of acute pain and anxiety 48 hours after primary total hip and knee arthroplasty. These results could prove useful for the design of interventions aimed at postsurgical pain and anxiety management.

Descending projections from the medullary dorsal reticular nucleus make synaptic contacts with spinal cord lamina I cells projecting to that nucleus: An electron microscopic tracer study in the rat

An ultrastructural study is made of the synaptic contacts occurring between structures labelled anterogradely and retrogradely in the superficial dorsal horn following injections of cholera toxin subunit B or horseradish peroxidase in the dorsal reticular nucleus of the medulla oblongata of the rat. Both tracers revealed labelled axonal boutons in lamina I with round synaptic vesicles and a few large granular vesicles making asymmetrical synaptic contacts upon labelled somata and dendrites. After injections of Phaseolus vulgaris leucoagglutinin in the dorsal reticular nucleus, labelled boutons identical to those revealed by the two other tracers were presynaptic to unlabelled somata and dendrites. In addition, dorsoreticular neurons were labelled retrogradely following injections of cholera toxin subunit B into the superficial dorsal horn of the cervical enlargement. These observations show the occurrence of a reciprocal connection between dorsal reticular and lamina I neurons. Considering the putative excitatory nature of the axodendritic contacts in lamina I, a positive feedback circuit is suggested, whereby the nociceptive signals transmitted to the dorsal medullary reticular formation by marginal neurons are intensified.

Risk Factors for Persistent Postsurgical Pain in Women Undergoing Hysterectomy Due to Benign Causes: A Prospective Predictive Study

UNLABELLED Persistent postsurgical pain (PPSP) is a major clinical problem with significant individual, social, and healthcare costs. The aim of this study was to examine the role of demographic, clinical, and psychological risk factors in the development of PPSP after hysterectomy due to benign disorders. In a prospective study, a consecutive sample of 186 women was assessed 24 hours before surgery (T1), 48 hours after surgery (T2), and 4 months after surgery (T3). Regression analyses were performed to identify predictors of PPSP. Four months after hysterectomy, 93 (50%) participants reported experiencing pain (numerical rating scale >0). Age, pain due to other causes, and type of hysterectomy emerged as significant predictive factors. Baseline presurgical psychological predictors identified were anxiety, emotional illness representation of the condition leading to surgery, and pain catastrophizing. Among the identified psychological predictors, emotional illness representation emerged as the strongest. Acute postsurgical pain frequency and postsurgical anxiety also revealed a predictive role in PPSP development. These results increase the knowledge on PPSP predictors and point healthcare professionals toward specific intervention targets such as anxiety (presurgical and postsurgical), pain catastrophizing, emotional illness representations, and acute pain control after surgery. PERSPECTIVE This study found that presurgical anxiety, emotional illness representations, and pain catastrophizing are risk factors for PPSP 4 months after hysterectomy, over and above age and clinical variables. These findings improve knowledge on PPSP and highlight potential intervention targets for healthcare professionals.

Risk factors for moderate and severe persistent pain in patients undergoing total knee and hip arthroplasty : a prospective predictive study

Persistent post-surgical pain (PPSP) is a major clinical problem with significant individual, social and health care costs. The aim of this study was to examine the joint role of demographic, clinical and psychological risk factors in the development of moderate and severe PPSP after Total Knee and Hip Arthroplasty (TKA and THA, respectively). This was a prospective study wherein a consecutive sample of 92 patients were assessed 24 hours before (T1), 48 hours after (T2) and 4–6 months (T3) after surgery. Hierarchical logistic regression analyses were performed to identify predictors of moderate and severe levels of PPSP. Four to six months after TKA and THA, 54 patients (58.7%) reported none or mild pain (Numerical Rating Scale: NRS ≤3), whereas 38 (41.3%) reported moderate to severe pain (NRS >3). In the final multivariate hierarchical logistic regression analyses, illness representations concerning the condition leading to surgery (osteoarthritis), such as a chronic timeline perception of the disease, emerged as a significant predictor of PPSP. Additionally, post-surgical anxiety also showed a predictive role in the development of PPSP. Pre-surgical pain was the most significant clinical predictive factor and, as expected, undergoing TKA was associated with greater odds of PPSP development than THA. The findings on PPSP predictors after major joint arthroplasties can guide clinical practice in terms of considering cognitive and emotional factors, together with clinical factors, in planning acute pain management before and after surgery.

Pronociceptive changes in response properties of rostroventromedial medullary neurons in a rat model of peripheral neuropathy

The spared nerve injury (SNI) model of peripheral neuropathy produces a robust and long‐lasting hypersensitivity. Previous behavioural studies suggest that brainstem–spinal pathways originating in or relaying through the rostroventromedial medulla (RVM) contribute to neuropathic hypersensitivity. We determined whether SNI induces changes in response properties of RVM neurons that might influence descending modulation of nociception. RVM neurons included in the study were classified into presumably pronociceptive ON‐cells and antinociceptive OFF‐cells (giving excitatory or inhibitory responses to noxious stimulation, respectively). Spontaneous activity and the response to cold, pinch and colorectal distension were assessed under light anaesthesia in the rat, 1 week and 8 weeks following nerve injury or sham operation. Spontaneous activity was increased 1 week but not 8 weeks after nerve injury in ON‐cells but decreased in OFF‐cells at both time points. In the SNI group, cold‐evoked responses were enhanced particularly in ON‐cells, independent of the postoperative time point. Responses of ON‐cells to pinch and visceral stimulation were enhanced 8 weeks but not 1 week following nerve injury, whereas OFF‐cell responses to pinch or colorectal distension were not changed. The results indicate that SNI induces pronociceptive changes in spontaneous activities of ON‐cells and OFF‐cells and peripherally evoked responses of ON‐cells that vary with the postoperative time point. Increased ON‐cell activity and decreased OFF‐cell activity in the RVM are likely to enhance spinal nociception in a tonic fashion, whereas increased responses of ON‐cells to peripheral stimulation are likely to enhance ascending nociceptive signals by a positive feedback following peripheral noxious stimulation.