Brain GABA and glutamate levels across pain conditions: A systematic literature review and meta-analysis of 1H-MRS studies using the MRS-Q quality assessment tool.

BACKGROUND: A proposed mechanism of chronic pain is dysregulation between the main inhibitory (GABA) and excitatory (glutamate) neurometabolites of the central nervous system. The level of these neurometabolites appears to differ in individual studies of people with pain compared to pain-free controls across different pain conditions. However, this has yet to be systematically investigated. AIMS: To establish whether GABA, glutamate, glutamine and Glx levels differ across pain conditions when compared to pain-free controls. METHODS: Five databases were searched. Studies were included if they investigated: 1) A pain condition compared to control. 2) Reported GABA, glutamate, glutamine or glutamate/glutamine level. 3) Used 1H-Magnetic Resonance Spectroscopy (Prospero Project ID CRD42018092170). Data extracted included neurometabolite level, pain diagnosis, and spectroscopy parameters. Meta-analyses were conducted to establish the difference in neurometabolite level between participants with pain and pain-free controls for different pain conditions. The MRS-Q was developed from existing clinical consensus to allow for the assessment of quality in the included studies. RESULTS: Thirty-five studies were included investigating combinations of migraine (n = 11), musculoskeletal pain (n = 8), chronic pain syndromes (n = 9) and miscellaneous pain (n = 10). Higher GABA levels were found in participants with migraine compared to controls (Hedge's G 0.499, 95%CI: 0.2 to 0.798). In contrast, GABA levels in musculoskeletal pain conditions (Hedge's G -0.189, 95%CI: 0.530 to 0.153) and chronic pain syndromes (Hedge's G 0.077, 95%CI: 1.612 to 1.459) did not differ from controls. Results for other brain neurometabolites revealed significantly higher levels for glutamate in participants with migraine and Glx in chronic pain syndromes compared to controls. CONCLUSION: These results support the theory that underlying neurometabolite levels may be unique in different pain conditions and therefore representative of biomarkers for specific pain conditions.

Pharmacokinetic and pharmacodynamic modeling for acute and chronic pain drug assessment.

INTRODUCTION: Population pharmacokinetic and pharmacodynamic (PK/PD) modeling is a critical component of drug development. Quantitative PK/PD models are used in drug development to improve both the design and interpretation of clinical trials across therapeutic areas. AREAS COVERED: In this review, the authors provide an overview of PK/PD modeling approaches and their applications in the management of acute and chronic pain as well as drug assessment. The advantages and limitations of these modeling approaches with regard to handling different end points of pain assessment in monotherapy and combination therapy are highlighted. EXPERT OPINION: New modeling approaches suitable for analgesics used in treatment of acute and chronic pain have started to emerge during the past few years. The application of the clinical utility index is limited but highly encouraged in pain drug assessment as it may inform the optimal window for treatment of pain to attain the best benefit:risk ratio. Owing to the restricted range of pain scores, beta regression models and coarsening models may be more appropriate modeling approaches for the bounded outcome data, rather than regular nonlinear/linear models that assume normal or lognormal error distribution. Additionally, modeling of exposure-response in flexible chronic pain studies remains challenging, and further investigations are needed.

Biochemical and pharmacological assessment of MAP-kinase signaling along pain pathways in experimental rodent models: a potential tool for the discovery of novel antinociceptive therapeutics.

Injury to the peripheral or central nervous system can induce changes within the nervous tissues that promote a state of sensitization that may underlie conditions of pathological chronic pain. A key biochemical event in the initiation and maintenance of peripheral and central neuronal sensitization associated with chronic pain is the phosphorylation and subsequent activation of mitogen-activated protein kinases (MAPKs) and immediate early gene transcription factors, in particular cAMP-response element binding protein (CREB). In this commentary we review the preclinical data that describe anatomical and mechanistic aspects of nociceptive-induced signaling along nociceptive pathways including peripheral cutaneous axons, the dorsal root ganglia, spinal cord dorsal horn and cerebral cortex. In addition to the regional manifestation of nociceptive signaling, investigations have attempted to elucidate the cellular origin of biochemical nociceptive processing in which communication, i.e. cross-talk between neurons and glia is viewed as an essential component of pathogenic pain development. Here, we outline a research strategy by which nociceptive-induced cellular signaling in experimental pain models, specifically MAPK and CREB phosphorylation can be utilized to provide mechanistic insight into drug-target interaction along the nociceptive pathways. We describe a series of studies using nociceptive inflammatory and neuropathic pain models to investigate the effects of known pain therapeutics on nociceptive-induced biochemical signaling and present this as a complementary research strategy for assessing antinociceptive activity useful in the preclinical development of novel pain therapeutics.

[Chronic pain: medico-biologic and sotsio-economic aspects].

In this article the role of neurobiological, psychological and social factors in pathogenesis of chronic pain is analyzed. The chronic pain is considered not as a symptom of damage of tissue and as independent illness due to non-adequate neuroplasticity of systems involved into regulation of pain sensitivity. The major role in development and maintenance of chronic pain is devoted to the primary genetically determined and/or secondary disturbance of interaction between nociceptive and antinociceptive systems at various levels--from peripheral neuron to central structures--that provides pain perception and painful behaviour development.