A Key Role of the Basal Ganglia in Pain and Analgesia - Insights Gained Through Human Functional Imaging

The basal ganglia (BG) are composed of several nuclei involved in neural processing related to the execution of motor, cognitive and emotional activities. Preclinical and clinical data have implicated a role for these structures in pain processing. Recently neuroimaging has added important information on BG activation in conditions of acute pain, chronic pain and as a result of drug effects. Our current understanding of alterations in cortical and sub-cortical regions in pain suggests that the BG are uniquely involved in thalamo-cortico-BG loops to integrate many aspects of pain. These include the integration of motor, emotional, autonomic and cognitive responses to pain

Case report: Chronic pain in a pediatric patient with late-onset pompe disease

Pompe disease (PD) is a rare inherited metabolic disorder of deficient or absent acid alpha-glucosidase (GAA), resulting in defective lysosomal glycogen catabolism. Muscle weakness, respiratory deficiency and gastrointestinal symptoms are commonly monitored in PD. However, pain and associated psychological symptoms are less focused upon. A pediatric patient with late-onset Pompe disease (LOPD) comorbid with chronic pain is presented. Symptoms of pain in the feet were first reported between 6 and 7 years of age and were attributed to growing pains. Following progression of lower body pain, weakness, fatigue, and difficulties with ambulation, a thorough clinical assessment including genetic testing was performed, which led to a diagnosis of LOPD at 9 years of age. ERT with recombinant human alglucosidase alfa was subsequently started. The patient’s clinical status is compounded by depressed mood, anxiety, and attention deficit hyperactivity disorder, which may further exacerbate pain. A multidisciplinary pain treatment approach consisting of orthopedics, physical therapy, and psychosocial therapy aimed at enhancing pain coping skills is described for this LOPD patient. This case highlights the need for a greater understanding of pain generation and identification of optimized pain treatment approaches in children with LOPD that can be implemented alongside ERT

Pain Facilitation Brain Regions Activated by Nalbuphine Are Revealed by Pharmacological fMRI

Nalbuphine, an agonist-antagonist kappa-opioid, produces brief analgesia followed by enhanced pain/hyperalgesia in male postsurgical patients. However, it produces profound analgesia without pain enhancement when co-administration with low dose naloxone. To examine the effect of nalbuphine or nalbuphine plus naloxone on activity in brain regions that may explain these differences, we employed pharmacological magnetic resonance imaging (phMRI) in a double blind cross-over study with 13 healthy male volunteers. In separate imaging sessions subjects were administered nalbuphine (5 mg/70 kg) preceded by either saline (Sal-Nalb) or naloxone 0.4 mg (Nalox-Nalb). Blood oxygen level-dependent (BOLD) activation maps followed by contrast and connectivity analyses revealed marked differences. Sal-Nalb produced significantly increased activity in 60 brain regions and decreased activity in 9; in contrast, Nalox-Nalb activated only 14 regions and deactivated only 3. Nalbuphine, like morphine in a previous study, attenuated activity in the inferior orbital cortex, and, like noxious stimulation, increased activity in temporal cortex, insula, pulvinar, caudate, and pons. Co-administration/pretreatment of naloxone selectively blocked activity in pulvinar, pons and posterior insula. Nalbuphine induced functional connectivity between caudate and regions in the frontal, occipital, temporal, insular, middle cingulate cortices, and putamen; naloxone co-admistration reduced all connectivity to non-significant levels, and, like phMRI measures of morphine, increased activation in other areas (e.g., putamen). Naloxone pretreatment to nalbuphine produced changes in brain activity possess characteristics of both analgesia and algesia; naloxone selectively blocks activity in areas associated with algesia. Given these findings, we suggest that nalbuphine interacts with a pain salience system, which can modulate perceived pain intensity

Default-Mode-Like Network Activation in Awake Rodents

During wakefulness and in absence of performing tasks or sensory processing, the default-mode network (DMN), an intrinsic central nervous system (CNS) network, is in an active state. Non-human primate and human CNS imaging studies have identified the DMN in these two species. Clinical imaging studies have shown that the pattern of activity within the DMN is often modulated in various disease states (e.g., Alzheimer's, schizophrenia or chronic pain). However, whether the DMN exists in awake rodents has not been characterized. The current data provides evidence that awake rodents also possess ‘DMN-like’ functional connectivity, but only subsequent to habituation to what is initially a novel magnetic resonance imaging (MRI) environment as well as physical restraint. Specifically, the habituation process spanned across four separate scanning sessions (Day 2, 4, 6 and 8). At Day 8, significant (p<0.05) functional connectivity was observed amongst structures such as the anterior cingulate (seed region), retrosplenial, parietal, and hippocampal cortices. Prior to habituation (Day 2), functional connectivity was only detected (p<0.05) amongst CNS structures known to mediate anxiety (i.e., anterior cingulate (seed region), posterior hypothalamic area, amygdala and parabracial nucleus). In relating functional connectivity between cingulate-default-mode and cingulate-anxiety structures across Days 2-8, a significant inverse relationship (r = −0.65, p = 0.0004) was observed between these two functional interactions such that increased cingulate-DMN connectivity corresponded to decreased cingulate anxiety network connectivity. This investigation demonstrates that the cingulate is an important component of both the rodent DMN-like and anxiety networks

A key role of the basal ganglia in pain and analgesia - insights gained through human functional imaging

Abstract The basal ganglia (BG) are composed of several nuclei involved in neural processing related to the execution of motor, cognitive and emotional activities. Preclinical and clinical data have implicated a role for these structures in pain processing. Recently neuroimaging has added important information on BG activation in conditions of acute pain, chronic pain and as a result of drug effects. Our current understanding of alterations in cortical and sub-cortical regions in pain suggests that the BG are uniquely involved in thalamo-cortico-BG loops to integrate many aspects of pain. These include the integration of motor, emotional, autonomic and cognitive responses to pain.</p

Neurocircuitry basis of the opioid use disorder-post-traumatic stress disorder comorbid state:conceptual analyses using a dimensional framework

Understanding the interface between opioid use disorder (OUD) and post-traumatic stress disorder (PTSD) is challenging. By use of a dimensional framework, such as research domain criteria, convergent and targetable neurobiological processes in OUD-PTSD comorbidity can be identified. We hypothesise that, in OUD-PTSD, circuitry that is implicated in two research domain criteria systems (ie, negative valence and cognitive control) underpins dysregulation of incentive salience, negative emotionality, and executive function. We also propose that the OUD-PTSD state might be systematically investigated with approaches outlined within a neuroclinical assessment framework for addictions and PTSD. Our dimensional analysis of the OUD-PTSD state shows how first-line therapeutic approaches (ie, partial μ-type opioid receptor [MOR1] agonism) modulate overlapping neurobiological and clinical features and also provides mechanistic rationale for evaluating polytherapeutic strategies (ie, partial MOR1 agonism, κ-type opioid receptor [KOR1] antagonism, and α-2A adrenergic receptor [ADRA2A] agonism). A combination of these therapeutic mechanisms is projected to facilitate recovery in patients with OUD-PTSD by mitigating negative valence states and enhancing executive control