Meta-Analysis of thirty-four independent samples studied using PET reveals a significantly attenuated central response to noxious stimulation in clinical pain patients

Chronic pain disorder is widely understood as a “biopsychosocial” phenomenon, meaning that it is influenced by psychology and certain life events. This broad understanding of chronic pain suggests that central responses during pain experience should be altered in patients compared with pain-free volunteers. A total of 34 studies are reviewed, revealing a widespread “neuromatrix” of activated regions. These regions include the brain stem, thalamus, and lentiform nucleus, and the insula, prefrontal, parietal, and anterior cingulate cortices. Meta-analysis of these studies does not reveal any single region or pattern of activity to be of particular influence during chronic pain but does reveal a generally reduced response to noxious stimulation in patients with concomitant clinical pain. The relevance of this finding remains unclear with the most parsimonious explanation being increased response variability in patients. More specific findings can be revealed when using a hypothesis-generated approach; further investigation of genetic and developmental predisposition is suggested.     

Analgesic antidepressants promote the responsiveness of locus coeruleus neurons to noxious stimulation: implications for neuropathic pain

Antidepressants that block the reuptake of noradrenaline and/or serotonin are among the first-line treatments for neuropathic pain, although the mechanisms underlying this analgesia remain unclear. The noradrenergic locus coeruleus is an essential element of both the ascending and descending pain modulator systems regulated by these antidepressants. Hence, we investigated the effect of analgesic antidepressants on locus coeruleus activity in Sprague-Dawley rats subjected to chronic constriction injury (CCI), a model of neuropathic pain. In vivo extracellular recordings of locus coeruleus revealed that CCI did not modify the basal tonic activity of this nucleus, although its sensory-evoked response to noxious stimuli was significantly altered. Under normal conditions, noxious stimulation evokes an early response, corresponding to the activation of myelinated A fibers, which is followed by an inhibitory period and a subsequent late capsaicin-sensitive response, consistent with the activation of unmyelinated C fibers. CCI provokes an enhanced excitatory early response in the animals and the loss of the late response. Antidepressant administration over 7 days (desipramine, 10mg/kg/day or duloxetine, 5mg/kg/day, delivered by osmotic minipumps) decreased the excitatory firing rate of the early response in the CCI group. Moreover, in all animals, these antidepressants reduced the inhibitory period and augmented the late response. We propose that N-methyl-d-aspartate and alpha-2-adrenoceptors are involved in the analgesic effect of antidepressants. Antidepressant-mediated changes were correlated with behavioral effects indicative of analgesia in healthy and neuropathic rats.