Pain matrices and neuropathic pain matrices: A review

Background: The delta opioid receptor (DOR) contributes to pain control, and a major challenge is the identification of DOR populations that control pain, analgesia, and tolerance. Astrocytes are known as important cells in the pathophysiology of chronic pain, and many studies report an increased prevalence of pain in women. However, the implication of astrocytic DOR in neuropathic pain and analgesia, as well as the influence of sex in this receptor activity, remains unknown.Experimental Approach: We developed a novel conditional knockout (cKO) mouse line wherein DOR is deleted in astrocytes (named GFAP-DOR-KO), and investigated neuropathic mechanical allodynia as well as analgesia and analgesic tolerance in mutant male and female mice. Neuropathic cold allodynia was also characterized in mice of both sexes lacking DOR either in astrocytes or constitutively.Results: Neuropathic mechanical allodynia was similar in GFAP-DOR-KO and floxed DOR control mice, and the DOR agonist SNC80 produced analgesia in mutant mice of both sexes. Interestingly, analgesic tolerance developed in cKO males and was abolished in cKO females. Cold neuropathic allodynia was reduced in mice with decreased DOR in astrocytes. By contrast, cold allodynia was exacerbated in full DOR KO females.Conclusions: These findings show that astrocytic DOR has a prominent role in promoting cold allodynia and analgesic tolerance in females, while overall DOR activity was protective. Altogether this suggests that endogenous- and exogenous-mediated DOR activity in astrocytes worsens neuropathic allodynia while DOR activity in other cells attenuates this form of pain. In conclusion, our results show a sex-specific implication of astrocytic DOR in neuropathic pain and analgesic tolerance. These findings open new avenues for developing tailored DOR-mediated analgesic strategies.

Here, the “pain matrix” is designed as a fluid system, made up of lots of networks interacting with each other. A nociceptive matrix receiving spinothalamic input (mainly the operculo-insular region) ensures the specific nature of somatic pain, and is the only thing that, if destroyed, results in selective impairment of heat and pain perception. The transition between a cortical nociception and conscious pain is dependent on a secondary network that includes at least the anterior, posterior parietal and prefrontal insular regions. These secondary regions are not specifically nociceptive: their stimulation does not lead to pain and when destroyed pain relief is not generated; their joint activation is necessary for the conscious perception of pain, its attentional modulation and the control of associated vegetative reactions. The immediate pain experience that ensues may even be transformed based on beliefs, emotions and expectations of the individual, through the activity of tertiary regions, including the perigeniculate cingulate, orbitofrontal and limbic networks. The pain that we remember is the result of continuous interactions between these sub-systems, and the substantial changes in the pain experience can be obtained by acting on each of them.

Changes in brain functional connectivity associated with ongoing neuropathic pain in patients with painful polyneuropathies.

SP66 Chemotherapy induced neuropathic pain. Clinical diagnosis and treatment

423-P: Altered Microvascular Perfusion of the Pain-Processing Areas of the Brain during the Experience of Spontaneous Neuropathic Pain

Preface/introduction

Physiology and Treatment of Pain

Similarity of suffering: Equivalence of psychological and psychosocial factors in neuropathic and non-neuropathic orofacial pain patients

The pathophysiology of central pain syndromes is still poorly understood and their treatment remains a major challenge. It has long been suggested that lesions of the spinothalamic pathways are necessary for developing these pain syndromes. The recently proposed thermosensory disinhibition theory suggests that reduction of the inhibition of thermal sensory afferents that affect nociceptive systems may play a major pathophysiological role. Syringomyelia, which is frequently associated with central neuropathic pain, is characterized by a selective or preferential lesion of the spinothalamic tract resulting in thermosensory deficits of various extents and magnitudes. Thus, syringomyelia represents a unique 'pathological model' particularly suited to investigating the relationship between spinothalamic tract dysfunction, thermosensory deficits and pain. Here, we systematically compared the sensory loss (thermal and mechanical), using quantitative sensory testing, between 46 consecutive syringomyelia patients with or without neuropathic pain. We then further investigated the mechanisms of evoked pains in these patients, using functional MRI (fMRI) in a subgroup of patients with cold or brush-evoked allodynia, compared with patients without pain and healthy volunteers. We found no significant difference in the magnitude or extent of sensory deficits between patients with or without neuropathic pain, suggesting that lesions of the spinothalamic pathways are not sufficient for developing central pain. However, a different pattern of sensory deficits was observed between patients with spontaneous pain only (n = 11) and patients with both spontaneous pain and allodynia (n = 20), suggesting that the mechanisms of central pain are not univocal. In patients with spontaneous pain only, the thermal sensory loss was significantly more asymmetrical and there was a direct relationship between the extent of thermosensory deficits (i.e. deafferentation) and the intensity of burning pain. In contrast, patients with allodynia had reduced thermal deficits, in terms of both magnitude and extent. In addition, the sensory deficits were different between patients with cold or tactile allodynia, suggesting distinct pathophysiological mechanisms related to the sub-modalities of allodynia. Our fMRI study further confirmed this, showing that different sub-types of allodynia were associated with distinct patterns of brain activity, which do not necessarily correspond to the 'pain matrix' involved in acute physiological pain. The prefrontal cortex was the only area consistently activated by pathological evoked pains, suggesting that alteration of high-level pain modulatory mechanisms might play a major role in allodynia due to central lesion.

Brain imaging of neuropathic pain

Chronic pain is highly prevalent in frail older adults, resulting in reduced mobility and poor quality of life. However, research on the experience of chronic pain among frail older adults is scarce.To compare the experience of chronic pain among frail, prefrail, and non-frail older adults, and to identify associations involving pain measures and frailty syndrome.We conducted a cross-sectional study with older adults aged ≥ 60 years presenting chronic pain. The participants were recruited by convenience in specialized outpatient services at public hospitals. Frailty syndrome was identified through the frailty phenotype. The experience of pain was compared among the groups, and we conducted a multivariate logistic regression analysis adjusted for covariates.Out of the 135 participants, 36.3% were non-frail, 38.5%, prefrail, and 25.2%, frail. Frail older adults presented severe pain more frequently (p = 0.009) and had worse scores for neuropathic pain (mean: 4.1; 95%CI: 3.2-5.1) and depression associated with chronic pain (mean: 9.7; 95%CI: 7.9-11.5) compared with non-frail older adults (p < 0.001). Moreover, frail older adults presented worse multidimensional pain scores (mean: 59.4; 95%CI: 51.7-67.2) compared with non-frail (p = 0.001) and prefrail older adults (p = 0.017). Frail older adults were 3.5-fold as likely to present neuropathic pain, and they presented a 7-fold higher risk of severe pain than non-frail and prefrail older adults.Frail older adults present severe chronic pain and experience neuropathic pain more frequently. Comprehensive chronic pain assessment and management in this population is critical to achieve active and healthy aging.

Neuropathic pain is common and distressing. Improved mechanistic understanding and pharmacotherapies are urgently needed. Molecularly specific pain syndromes may provide insights with translational relevance. Glycine receptors are known to play a key role in inhibitory neurotransmission in the spinal dorsal horn and have therefore been considered as targets for analgesic development. While autoantibodies directed against glycine receptors may rarely arise spontaneously in humans, a detailed phenotype of neuropathic pain and allodynia in association with these autoantibodies has not been described. We describe the case of a previously well adult presenting with severe neuropathic pain and allodynia as part of an autoimmune brainstem and spinal syndrome with glycine receptor autoantibodies. Our patient experienced a severe illness, including marked neuropathic pain and allodynia, hypoventilation, tetraparesis, and ophthalmoplegia. A diagnosis of progressive encephalomyelitis with rigidity and myoclonus was made. Neuropathic pain was characterized with validated instruments and responded promptly to cause-directed immunotherapy. A detailed longitudinal phenotyping, using validated pain measurement instruments, of severe neuropathic pain and allodynia associated with likely pathogenic glycine receptor autoantibodies is reported. This case may have relevance for translational development of analgesics targeting glycinergic neurotransmission.

INTRODUCTION Investigation of the neural responses of chronic pain have traditionally involved establishing the BOLD fMRI response to acute pain in a nodal network that has been referred to as the ‘pain matrix’ or the ‘pain neuromatrix’ (1). However, Melzack originally used the term ‘matrix’ because the system to which he referred was multimodal in function and lacked specificity. This might explain why, over 20 years after the term was coined, there has been little translational benefit to patients in terms of improved management of chronic pain states despite numerous studies examining the ‘pain matrix response’. The basal ganglia form part of this matrix and are worthy of further investigation. Destruction of nigrostriatal neurones in the ventral basal ganglia are associated with reduced pain thresholds, the inverse effect occurring with nigrostriatal stimulation(2). However, inactivation of the accumbens core in the ventral basal ganglia with local anaesthetic has demonstrated a hyperalgesic response (3). Molecular imaging has been used to examine the differential roles of dorsal and ventral basal ganglia in pain perception (4) . These authors found that whilst nigrostriatal D2-dopamine activity correlates with sensory and affective ratings, in accumbens the dopamine response is positively associated with negative affect and fear ratings during pain, aspects of the pain experience that are thought to better explain interindividual variations in chronic pain (5) and response to analgesia. In establishing a region of interest approach to the investigation of chronic pain through the application of acutely painful stimuli, the ventral striatum may therefore be an important target. The role of the ventral striatum in response to aversive stimuli is receiving increasing attention, in counterpart to studies of its responsivity to rewarding stimuli. Recent work (6) suggests that the differential striatal responses to acute pain may provide a meaningful insight into the neural substrates of chronic pain perception, including idiopathic pain disorders and the functional somatic syndromes, where activation of the ‘pain matrix’ as a whole has proved unable to. We have investigated the brain response to somatosensory pain, specifically examining the response of the ventral striatum in contrast to other components of the ‘pain matrix’.

Deep brain stimulation for chronic pain: a narrative review.

Despite clear advancements in our understanding of the genesis of central pain (CP) [1,2], four notions continue to stand out in the neuropathic pain literature that—we will argue—must be thoroughly revised, if not discarded. We will refer to them as Pain Myths. In light of the supposed failures of cortectomies or thalamotomies to relieve phantom percepts and pain, Melzack [3] proposed that the anatomical substrate of the physical self is a network of neurons that extends throughout widespread areas of the brain ( Neuromatrix ). The repeated cyclical processing and synthesis of nerve impulses in the neuromatrix imparts a characteristic pattern ( neurosignature ) produced by the pattern of synaptic connections in the entire neuromatrix. Neuromodules of the matrix are dedicated to process specialized sensory events, which impress subsignatures on the larger one. This active neuromatrix, when deprived of modulating inputs, produces an abnormal signature pattern that subserves the different qualities of, e.g., neuropathic pain. Ever since 1991, many investigators concluded that the neurosignature of pain is dependent on a core neuromodule of four cortical areas: primary somatosensory cortex (SI), secondary somatosensory cortex (SII), insula and anterior cingulate cortex (ACC), the so-called pain matrix (e.g., [4]). A review of imaging studies concluded that “ acute physiological pain and neuropathic pain have distinct although overlapping brain activation patterns, but there is no unique “pain matrix” or “allodynia network” ” [5]. Importantly, conclusive evidence [6] has emerged that this so-called pain matrix is actually a multimodal network related to the detection of and reaction to salient sensory inputs, regardless of whether these sensory events are conveyed by nociceptive pathways or are perceived as painful: “ the neural activity recorded in the so-called ‘pain matrix’ cannot be considered as a direct correlate of the conscious perception of a somatosensory stimulus as painful ” [7] …