Mol Pain
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Chronic pain remains a significant clinical problem despite substantial advances in our understanding of how persistent nociceptor stimulation drives plasticity in the CNS. A major theme that has emerged in this area of work is the strong similarity between plasticity involved in learning and memory in CNS regions such as cortex and hippocampus with mechanisms underlying chronic pain development and maintenance in the spinal dorsal horn and other CNS areas such as anterior cingulate cortex (ACC). We, and others have recently implicated an atypical PKC (aPKC), called PKMζ, in the maintenance of pain plasticity based on biochemical assays and the use of a peptide pseudosubstrate inhibitor called ZIP. ⋯ Here we critically review the evidence that PKMζ might represent a new target for the reversal of certain chronic pain states. Furthermore, we consider whether ZIP might have other aPKC or even non-aPKC targets and the significance of such off-target effects for evaluating maintenance mechanisms of chronic pain. We conclude that, current controversies aside, utilization of ZIP as a tool to interrogate maintenance mechanisms of chronic pain and further investigations into the potential role of PKMζ, and other aPKCs, in pain plasticity are likely to lead to further insights with the potential to unravel the enigma that is the disease of chronic pain.
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GTP cyclohydrolase 1 (GTP-CH1), the rate-limiting enzyme in the synthesis of tetrahydrobiopterin (BH4), encoded by the GCH1 gene, has been implicated in the development and maintenance of inflammatory pain in rats. In humans, homozygous carriers of a "pain-protective" (PP) haplotype of the GCH1 gene have been identified exhibiting lower pain sensitivity, but only following pain sensitisation. Ex vivo, the PP GCH1 haplotype is associated with decreased induction of GCH1 after stimulation, whereas the baseline BH4 production is not affected. Contrary, loss of function mutations in the GCH1 gene results in decreased basal GCH1 expression, and is associated with DOPA-responsive dystonia (DRD). So far it is unknown if such mutations affect acute and inflammatory pain. ⋯ In this study, we demonstrate novel evidence that genetic mutations in the GCH1 gene modulate pain-like hypersensitivity. Together, the present data suggest that BH4 is not important for basal heat and mechanical pain, but they support the hypothesis that BH4 plays a role in inflammation-induced hypersensitivity. Our studies suggest that the BH4 pathway could be a therapeutic target for the treatment of inflammatory pain conditions. Moreover, the hph-1 mice provide a valid model to study the consequence of congenital deficiency of GCH1 in painful conditions.
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Corticotropin-releasing factor (CRF) plays an important role in affective states and disorders. CRF is not only a "stress hormone" but also a neuromodulator outside the hypothalamic-pituitary-adrenocortical (HPA) axis. The amygdala, a brain center for emotions, is a major site of extrahypothalamic expression of CRF and its G-protein-coupled receptors. Our previous studies showed that endogenous activation of CRF1 receptors in an arthritis pain model contributes to amygdala hyperactivity and pain-related behaviors. Here we examined the synaptic and behavioral effects of CRF in the amygdala of normal animals in the absence of tissue injury or disease. ⋯ Non-pain-related activation of CRF1 receptors in the amygdala can trigger pain-responses in normal animals through a mechanism that involves PKA-dependent synaptic facilitation in CeLC neurons independent of HPA axis function. The results suggest that conditions of increased amygdala CRF levels can contribute to pain in the absence of tissue pathology or disease state.