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Measuring altered nociceptive processing involved in chronic pain is difficult due to a lack of objective methods. Potential methods to characterize human nociceptive processing involve measuring neurophysiological activity and psychophysical responses to well-defined stimuli. To reliably measure neurophysiological activity in response to nociceptive stimulation using EEG, synchronized activation of nerve fibers and a large number of stimuli are required. On the other hand, to reliably measure psychophysical detection thresholds, selection of stimulus amplitudes around the detection threshold and many stimulus–response pairs are required. Combining the two techniques helps in quantifying the properties of nociceptive processing related to detected and non-detected stimuli around the detection threshold.The two techniques were combined in an experiment including 20 healthy participants to study the effect of intra-epidermal electrical stimulus properties (i.e. amplitude, single- or double-pulse and trial number) on the detection thresholds and vertex potentials. Generalized mixed regression and linear mixed regression were used to quantify the psychophysical detection probability and neurophysiological EEG responses, respectively.It was shown that the detection probability is significantly modulated by the stimulus amplitude, trial number, and the interaction between stimulus type and amplitude. Furthermore, EEG responses were significantly modulated by stimulus detection and trial number. Hence, we successfully demonstrated the possibility to simultaneously obtain information on psychophysical and neurophysiological properties of nociceptive processing. These results warrant further investigation of the potential of this method to observe altered nociceptive processing.

The central amygdala (CE) emerges as a critical node for affective processing. However, how CE local circuitry interacts with brain wide affective states is yet uncharted. Using basic nociception as proxy, we find that gene expression suggests diverging roles of the two major CE neuronal populations, protein kinase C δ-expressing (PKCδ+) and somatostatin-expressing (SST+) cells. Optogenetic (o)fMRI demonstrates that PKCδ+/SST+ circuits engage specific separable functional subnetworks to modulate global brain dynamics by a differential bottom-up vs. top-down hierarchical mesoscale mechanism. This diverging modulation impacts on nocifensive behavior and may underly CE control of affective processing., In order to examine how central amygdala (CE) local circuitry interacts with brain-wide affective states, Wank et al performed gene expression analysis and optogenetic fMRI in mice, using basic nociception as a proxy. They found evidence for diverging roles of two major CE neuronal populations in modulating global brain states, which impacts on aversive processing and nocifensive behaviour.

Pain disorders can be initiated and maintained by malfunctioning of one or several mechanisms underlying the nociceptive function. Psychophysical procedures allow the estimation of nociceptive detection thresholds using intra-epidermal electrical stimuli. By varying the temporal properties of electrical stimuli, various contributions of nociceptive processes to stimulus processing can be observed. To observe the responsiveness of nociceptive thresholds to changes in nociceptive function, a model of capsaicin-induced nerve defunctionalization was used. Its effect on nociceptive detections thresholds was investigated over a period of 84 days. A cutaneous capsaicin (8 %) patch was applied for 60 min to the upper leg of eight healthy human participants. Single- and double-pulse electrical stimuli were presented in a pseudo-random order using an intra-epidermal electrode. Stimuli and corresponding responses were recorded on both treated and untreated skin areas prior to capsaicin application and on days 2, 7, 28, and 84. Increases in electrical detection thresholds at the capsaicin area were observed on days 2 and 7 for single-pulse stimuli. Detection thresholds corresponding to double-pulse stimuli were increased on days 7 and 28, suggesting a delayed and longer lasting effect on double-pulse stimuli. In the present study, it was demonstrated that the responsiveness of detection thresholds to capsaicin application depends on the temporal properties of electrical stimuli. The observation of capsaicin-induced changes by estimation of detection thresholds revealed different time patterns of contributions of peripheral and central mechanisms to stimulus processing.

Pain research is based broadly on physiological disciplines and its development follows the methodological progress of the era, from classical psychophysiology to electrophysiological investigations at peripheral and central nociceptive systems, single cells and ion channels to modern imaging of nociceptive processing. Physiological pain research in Germany has long been part of an interdisciplinary research network extending beyond all political boundaries, and this situation has continued since molecular techniques started to dominate all biomedical research. Current scientific questions, such as intracellular nociceptive signal mechanisms, interactions with other physiological systems including the immune system, or the genetic basis of epidemic and chronic pain diseases can only be solved interdisciplinary and with international collaboration.

The use of amphibian and mammalian in vitro spinal cord preparations, e.g., hemisected cord and transverse slices, has gained in popularity over the years due to the flexibility and ease of use of such preparations compared to classical in vivo approaches. When combined with modern experimental methodologies, such as patch clamping of visualized single cells or post-experimental neuroanatomy, this approach provides a powerful addition to the armamentarium available to study nociceptive processing in the dorsal horn. Some of these novel experimental approaches and the insight into nociception that they have provided are described below.

Headaches are among the most frequent symptoms for which Americans seek physician advice and treatment. Although headache may herald a serious underlying organic or psychological illness, it more commonly represents a primary disorder of brain stem nociceptive processing and modulation. Chronic daily headache characteristically develops gradually from episodic tension or migraine-type headaches into a refractory syndrome often associated with medication overuse and disability. Better understanding of the pathophysiology and evolutionary mechanisms involved in the development of chronic headache has led to recommended changes in nosology originally proposed by the International Headache Society (IHS). Recent scientific and clinical observations prompting revised classification have also led to the integration of pathoanatomic models, which explain persistent headache. Strategies for the management of chronic craniofacial pain should emphasize key behavioral and attitudinal changes and avoidance of medication overusage.

This article summarizes current knowledge regarding the involvement of cholinergic mechanisms of the central nervous system in transmission and modulation of nociceptive information, with emphasis on the spinal nociceptive processing. Major topics reviewed include the antinociceptive activity of cholinergic drugs, experimental evidence of the presence of the central cholinergic systems, subclasses of muscarinic receptors involved in antinociceptive effects, and a possible physiologic role of the central cholinergic mechanisms.