[Nociplastic pain in research and practice : Overview of biopsychosocial principles, possibilities and difficulties]. / Noziplastischer Schmerz in Forschung und Praxis : Übersicht über biopsychosoziale Grundlagen, Möglichkeiten und Schwierigkeiten.

Traditionally, two mechanistic pain categories were distinguished: nociceptive and neuropathic pain. After the definitions of these two mechanistic descriptors were refined more precisely in the International Association for the Study of Pain (IASP) taxonomy in 2011, a large group of patients remained whose pain could not be assigned to either of the two categories. Nociplastic pain was therefore proposed as a third mechanistic descriptor in 2016. This review article presents the current state of the integration of nociplastic pain into research and clinical practice. In particular, the possibilities and difficulties of applying this concept are addressed from a human and animal experimental research perspective.

Spinal cord fractalkine (CX3CL1) signaling is critical for neuronal sensitization in experimental nonspecific, myofascial low back pain.

Neuroactive substances released by activated microglia contribute to hyperexcitability of spinal dorsal horn neurons in many animal models of chronic pain. An important feedback loop mechanism is via release of fractalkine (CX3CL1) from primary afferent terminals and dorsal horn neurons and binding to CX3CR1 receptors on microglial cells. We studied the involvement of fractalkine signaling in latent and manifest spinal sensitization induced by two injections of nerve growth factor (NGF) into the lumbar multifidus muscle as a model for myofascial low back pain. Single dorsal horn neurons were recorded in vivo to study their receptive fields and spontaneous activity. Under intrathecal vehicle application, the two NGF injections led to an increased proportion of neurons responding to stimulation of deep tissues (41%), to receptive field expansion into the hindlimb (15%), and to resting activity (53%). Blocking fractalkine signaling by continuous intrathecal administration of neutralizing antibodies completely prevented these signs of spinal sensitization to a similar extent as in a previous study with the microglia inhibitor minocycline. Reversely, fractalkine itself induced similar sensitization in a dose-dependent manner (for 200 ng/mL: 45% deep tissue responses, 24% receptive field expansion, and 45% resting activity) as repeated nociceptive stimulation by intramuscular NGF injections. A subsequent single NGF injection did not have an additive effect. Our data suggest that neuron-to-microglia signaling via the CX3CL1-CX3CR1 pathway is critically involved in the initiation of nonspecific, myofascial low back pain through repetitive nociceptive stimuli.NEW & NOTEWORTHY Blocking fractalkine signaling by neutralizing antibodies completely prevented spinal sensitization induced by repetitive mild nociceptive input [2 nerve growth factor (NGF) injections into the multifidus muscle] Conversely, fractalkine given intrathecally caused the same pattern of spinal sensitization as the nociceptive NGF injections. Fractalkine signaling is critically involved in sensitization of dorsal horn neurons induced by repeated nociceptive low back muscle stimulation and may hence be a potential target for the prevention of nonspecific, myofascial low back pain.

Challenges of neuropathic pain: focus on diabetic neuropathy.

Neuropathic pain is a frequent condition caused by a lesion or disease of the central or peripheral somatosensory nervous system. A frequent cause of peripheral neuropathic pain is diabetic neuropathy. Its complex pathophysiology is not yet fully elucidated, which contributes to underassessment and undertreatment. A mechanism-based treatment of painful diabetic neuropathy is challenging but phenotype-based stratification might be a way to develop individualized therapeutic concepts. Our goal is to review current knowledge of the pathophysiology of peripheral neuropathic pain, particularly painful diabetic neuropathy. We discuss state-of-the-art clinical assessment, validity of diagnostic and screening tools, and recommendations for the management of diabetic neuropathic pain including approaches towards personalized pain management. We also propose a research agenda for translational research including patient stratification for clinical trials and improved preclinical models in relation to current knowledge of underlying mechanisms.