Chronic Pain

In order to investigate the molecular and cellular mechanisms for pain-related plasticity in the ACC, we decided to use genetic approaches together with integrative neuroscience techniques. First, we wanted to test if persistent pain may be enhanced by genetically enhanced NMDA receptor function, a key mechanism for triggering central plasticity in the brain4. Functional NMDA receptors contain heteromeric combinations of the NR1 subunit plus one or more of NR2A-D. While NR1 shows a widespread distribution in the brains, NR2 subunits exhibit regional distribution. In humans and rodents, NR2A and NR2B subunits predominate in forebrain structure. NR2A and NR2B subunits confer distinct properties to NMDA receptors; heteromers containing NR1 plus NR2B mediate a current that decays three to four times more slowly than receptors composed of NR1 plus NR2A. Unlike other ionotropic channels, NMDA receptors are 5-10 times more permeable to Ca2+ than to Na+ or K+. NMDA receptor-mediated currents are long lasting compared with the rapidly desensitizing kinetics of AMPA and KA receptor channels. In transgenic mice with forebrain-targeted NR2B overexpression, the normal developmental change in NMDA receptor kinetics was reversed45. NR2B subunit expression was observed extensively throughout the cerebral cortex, striatum, amygdala, and hippocampus, but not in the thalamus, brainstem, or cerebellum. In both the ACC and insular cortex, NR2B expression was significantly increased, and NMDA receptor-mediated responses were enhanced46. However, NMDA receptor-mediated responses in the spinal cord were not affected. NR2B transgenic and wild-type mice were indistinguishable in tests of acute nociception, but NR2B transgenic mice exhibited enhanced behavioral responses after peripheral injection of formalin. Late phase nociceptive responses but not early responses were enhanced. Furthermore, mechanical allodynia measured in the complete Freund's adjuvant (CFA) model (i.e., behavioral withdrawal responses to a non-noxious stimulus) were significantly enhanced in NR2B transgenic mice. These findings provide the first genetic evidence that forebrain NMDA receptors play a critical role in chronic pain.

Figure 25.3. Signaling Pathways from the Postsynaptic Membrane to the Nuclei that Lead to LTP in the ACC. Neural activity triggered by injury releases glutamate in the ACC synapses. Subsequent to activation of glutamate NMDA receptors, Ca2+ binds to CaM and leads to activation of calcium-stimulated ACs, including AC1 and AC8 and Ca2+/CaM dependent protein kinases (PKC, CaMKII, and CaMKIV). Activation of CaMKIV, a kinase predominantly expressed in the nuclei, will trigger CaMKIV-dependent CREB. In addition, activation of AC1 and AC8 leads to activation of PKA, and subsequently CREB. CREB and other immediate early genes (e.g., Egr1) in turn activate targets that are thought to lead to more permanent structural changes. Inset: the simplified neuronal network for sensory synaptic transmission, plasticity, and regulation in the central nervous system. DRG: dorsal root ganglion.

Figure 25.3. Signaling Pathways from the Postsynaptic Membrane to the Nuclei that Lead to LTP in the ACC. Neural activity triggered by injury releases glutamate in the ACC synapses. Subsequent to activation of glutamate NMDA receptors, Ca2+ binds to CaM and leads to activation of calcium-stimulated ACs, including AC1 and AC8 and Ca2+/CaM dependent protein kinases (PKC, CaMKII, and CaMKIV). Activation of CaMKIV, a kinase predominantly expressed in the nuclei, will trigger CaMKIV-dependent CREB. In addition, activation of AC1 and AC8 leads to activation of PKA, and subsequently CREB. CREB and other immediate early genes (e.g., Egr1) in turn activate targets that are thought to lead to more permanent structural changes. Inset: the simplified neuronal network for sensory synaptic transmission, plasticity, and regulation in the central nervous system. DRG: dorsal root ganglion.

Next, we wanted to know if inhibition of NMDA receptor dependent, calcium-stimulated signaling pathways in the ACC would help reduce chronic pain while keeping acute pain sensation intact (critical for animal or human self-protection). AC1 and AC8, the two major CaM-stimulated ACs in the brain, couple NMDA receptor activation to cAMP signaling pathways. In the ACC, strong and homogeneous patterns of AC1 and AC8 expression were observed in all cell layers47. Behavioral studies found that wild-type, AC1, AC8, or AC1&AC8 double knockout mice were indistinguishable in tests of acute pain including the tail-flick test, hot-plate test, the mechanical withdrawal responses. However, behavioral responses to a peripheral injection of two inflammatory stimuli, formalin and CFA, were reduced in AC1 or AC8 single knockout mice. Deletion of both AC1 and AC8 in AC1&AC8 double knockout mice produced the greatest reduction in persistent pain47. Importantly, microinjection of an AC activator, forskolin, can rescue defects in chronic pain in AC1 and AC8 double knockout mice. Consistently, pharmacological intervention at NMDA receptors as well as cAMP signaling pathways within the ACC also produced inhibitory effects on persistent pain in normal and wild-type animals, supporting the roles of ACC in persistent pain. Microinjection of NMDA receptor antagonists or PKA inhibitors reduced or blocked mechanical allodynia related to inflammation47. A recent study showed that persistent pain induced by tissue inflammation or nerve injury was significantly reduced in PSD-93 knockout mice, in part due to the lower level of NR2B expression at the spinal and cortical levels48.

Natural Pain Management

Natural Pain Management

Do You Suffer From Chronic Pain? Do You Feel Like You Might Be Addicted to Pain Killers For Life? Are You Trapped on a Merry-Go-Round of Escalating Pain Tolerance That Might Eventually Mean That No Pain Killer Treats Your Condition Anymore? Have you been prescribed pain killers with dangerous side effects?

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