Justus Benrath

Synaptic scaffolding protein Homer1a protects against chronic inflammatory pain.

Glutamatergic signaling and intracellular calcium mobilization in the spinal cord are crucial for the development of nociceptive plasticity, which is associated with chronic pathological pain. Long-form Homer proteins anchor glutamatergic receptors to sources of calcium influx and release at synapses, which is antagonized by the short, activity-dependent splice variant Homer1a. We show here that Homer1a operates in a negative feedback loop to regulate the excitability of the pain pathway in an activity-dependent manner. Homer1a is rapidly and selectively upregulated in spinal cord neurons after peripheral inflammation in an NMDA receptor–dependent manner. Homer1a strongly attenuates calcium mobilization as well as MAP kinase activation induced by glutamate receptors and reduces synaptic contacts on spinal cord neurons that process pain inputs. Preventing activity-induced upregulation of Homer1a using shRNAs in mice in vivo exacerbates inflammatory pain. Thus, activity-dependent uncoupling of glutamate receptors from intracellular signaling mediators is a novel, endogenous physiological mechanism for counteracting sensitization at the first, crucial synapse in the pain pathway. Furthermore, we observed that targeted gene transfer of Homer1a to specific spinal segments in vivo reduces inflammatory hyperalgesia. Thus, Homer1 function is crucially involved in pain plasticity and constitutes a promising therapeutic target for the treatment of chronic inflammatory pain.

Erasure of a Spinal Memory Trace of Pain by a Brief, High-Dose Opioid Administration

Long-Lasting Pain Killers Opioids are among the most widely used and extensively studied drugs in the world. A continuous application of relatively low opioid doses is thought to be necessary to maintain synaptic depression in pain pathways. Drdla-Schutting et al. (p. 235) found that a single opioid application could produce lasting reversal of synaptic long-term potentiation in pain pathways. Chronic pain is often associated with synaptic potentiation in nociceptive pathways. A brief, high-dose application of opioids depotentiated long-term potentiation in spinal pain pathways. The same dose also reversed hyperalgesia in behaving animals. Thus, opioids not only attenuate pain but also may eradicate a significant cause for chronic pain. Opioid administration turns down a pain amplifier by reversing synaptic long-term potentiation in spinal nociceptive pathways. Painful stimuli activate nociceptive C fibers and induce synaptic long-term potentiation (LTP) at their spinal terminals. LTP at C-fiber synapses represents a cellular model for pain amplification (hyperalgesia) and for a memory trace of pain. μ-Opioid receptor agonists exert a powerful but reversible depression at C-fiber synapses that renders the continuous application of low opioid doses the gold standard in pain therapy. We discovered that brief application of a high opioid dose reversed various forms of activity-dependent LTP at C-fiber synapses. Depotentiation involved Ca2+-dependent signaling and normalization of the phosphorylation state of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. This also reversed hyperalgesia in behaving animals. Opioids thus not only temporarily dampen pain but may also erase a spinal memory trace of pain.

Low Doses of Fentanyl Block Central Sensitization in the Rat Spinal Cord In Vivo

Background: μ-Opioid receptor agonists are strong analgesics. However, their usefulness for preemptive analgesia is controversial. The authors tested antinociceptive and preemptive properties of fentanyl as a μ-opioid receptor agonist in a model of spinal nociception in vivo. Methods: C fiber–evoked potentials were recorded in the superficial laminae I–II of the rat lumbar spinal cord with glass microelectrodes in response to electrical stimulation of the sciatic nerve. High-frequency stimulation was applied on the sciatic nerve to induce long-term potentiation of C fiber–evoked field potentials, a form of central sensitization. To test the effect of fentanyl on acute nociception, fentanyl was infused intravenously at increasing doses (6–192 μg · kg−1 · h−1). One hour after start of infusion, high-frequency stimulation was applied to evaluate effects of fentanyl on the induction of long-term potentiation. Results: In the absence of fentanyl, high-frequency stimulation potentiated C fiber–evoked field potentials to 149 ± 12% of controls (mean ± SEM; n = 6) for at least 1 h. Increasing doses of fentanyl led to a significant reduction of C fiber–evoked potentials in a dose-dependent manner. The induction of long-term potentiation was blocked by low doses of fentanyl (infusion 12–48 μg · kg−1 · h−1). At high doses, fentanyl did not block the induction of long-term potentiation (infusion 96–192 μg · kg−1 · h−1). Conclusions: Low doses of fentanyl block the synaptic form of central sensitization in the rat spinal cord in vivo, but higher doses do not have this effect.

Xenon blocks the induction of synaptic long-term potentiation in pain pathways in the rat spinal cord in vivo.

BACKGROUND:Xenon’s (Xe) mechanisms for producing anesthesia and analgesia are not fully understood. We tested the effect of Xe equilibrated in a lipid formulation or normal saline on spinal C-fiber-evoked potentials and on the induction of synaptic long-term potentiation (LTP). METHODS:C-fiber-evoked field potentials were recorded in the superficial lumbar spinal cord in response to supramaximal electrical stimulation of the sciatic nerve. Anesthesia was maintained with isoflurane in one-third O2 and two-thirds N2O. Xe equilibrated at a concentration of 600 &mgr;L/mL of Lipofundin MCT® 20%, (n = 5) or solvent alone (n = 3), and Xe equilibrated at a concentration of 100 &mgr;L/mL of normal saline (n = 7) or saline alone (n = 7) was given IV under apnea. High-frequency stimulation of the sciatic nerve was applied 60 min after the injection of Xe-containing formulations or solvents [to induce LTP]. RESULTS:High-frequency stimulation potentiated C-fiber-evoked potentials to 156% ± 14% (mean ± sem) of control. Low-dose Xe in saline 0.9% blocked the induction of LTP. High-dose Xe equilibrated in MC® 20% showed no additional effect when compared with the solvent, which blocked the induction of LTP. CONCLUSION:Low-dose Xe in saline 0.9% revealed no antinociceptive, but preventive, action in spinal pain pathways.

The mechanical properties of continuous spinal small-bore catheters.

Continuous spinal anesthesia (CSA) has a nearly 100-yr history. In situations of difficult removal of a CSA small-bore catheter, mechanical properties of the different catheters might be important, because breakage could occur. We compared 5 different CSA small-bore catheters, 22- to 28-gauge from 3 manufacturers, for tensile strength, tensile stress, distension, and yield strength. Maximal tensile strength is the force applied before breakage of the catheter. The material characteristics of different CSA small-bore catheters for maximal tensile strength were: 22-gauge = 29.56 ± 1.56 (mean ± sd) Newton (N), 24-gauge = 16.77 ± 1.61 N, 25-gauge = 9.20 ± 0.48 N, 27-gauge = 4.61 ± 0.25 N, 28-gauge = 5.07 ± 0.59 N at room temperature. A strong correlation between maximal tensile strength and the outer diameter (r = 0.957, P < 0.001) and maximal tensile strength and the wall thickness (r = 0.9, P < 0.001) was observed. Although extrapolation from experimental studies to clinical routine should be made with care, our data suggest that catheters with higher-strength characteristics may reduce the risk of catheter breakage in patients, although clinical correlations are lacking.

Das nozizeptive System von Früh- und Neugeborenen

Scheinbar harmlose Schmerzreize konnen bei Fruhund Neugeborenen das nozizeptive System fur Monate oder Jahre ungunstig beeinflussen (Porter et al. 1999). So zeigen Neugeborene, bei denen eine Zirkumzision ohne ausreichende Schmerzbehandlung vorgenommen wurde, auch noch Monate spater generell erniedrigte Schmerzschwellen (Taddio et al. 1997). Neuere Arbeiten bestatigen, dass bei Fruh- und Neugeborenen Hyperalgesie und Allodynie nicht nur durch grose Traumata, z.B. bei Operationen, sondern bereits durch kleinere schmerzhafte Eingriffe, z. B. solche zu diagnostischen Zwecken oder bei der intensivmedizinischen Behandlung, ausgelost werden konnen (Abdulkader et al. 2008; Porter et al. 1999; Schmelzle-Lubiecki et al. 2007). Andererseits konnen Fruhgeborene, die wahrend der Zeit der Intensivbehandlung einer Reihe von schmerzhaften Stimuli ausgesetzt sind, im spateren Leben auch unphysiologisch hohe Schmerzschwellen entwickeln (Grunau et al. 1994; Johnston u. Stevens 1996; Schmelzle-Lubiecki et al. 2007).

Nozizeptives System von Früh- und Neugeborenen

Das nozizeptive System ist in den ersten Lebenswochen extremen Reifungsprozessen unterworfen, die das periphere sensible Nervensystem, die spinale Reizubertragung und die supraspinale Schmerzverarbeitung ebenso betreffen wie die segmentale und absteigende Schmerzhemmung. Dabei spielen Veranderungen der exzitatorischen und inhibitorischen Neurotransmitter eine wichtige Rolle. Schon kleine Fruhgeborene sind zur Nozizeption fahig, die Inhibition ist wenig ausgebildet. Es besteht die Gefahr der Entwicklung pathologischer Schmerzzustande (Sensibilisierung). Diese gilt es durch eine adaquate Therapie zu vermeiden.

353 SYNAPTIC SCAFFOLDING PROTEIN HOMER1A PROTECTS AGAINST INFLAMMATORY PAIN

was performed to isolate spinal cord from supraspinal structures. Noxious stimuli were applied to peripheral receptive field to evoke responses from isolated wide dynamic range (WDR) neurones in 4min cycles. CP-101,606 (iv) was then administered cumulatively (8min cycles) until >50% reduction in responses were observed and ED50 values calculated. Results: In animals with inflammation and an intact spinal cord, CP-101,606 (25–400mmol/kg) dose-dependently inhibited noxious stimuli evoked firing, with an ED50 of 188mmol/kg. In animals with a transected spinal cord, CP-101,606 (100–600mmol/kg) had no effect. In animals with neuropathy, CP-101,606 (20–320mmol/kg) produced dosedependant inhibition of noxious stimuli evoked firing in animals with an intact and transected spinal cord; ED50 values were 195 mmol/kg and 148mmol/kg respectively. Conclusions: Spinal cord NR2B containing NMDA receptors contribute to the antinociceptive activity of CP-101,606 in model of neuropathic, but not inflammatory, pain demonstrating differential roles for spinal NR2B containing NMDA receptors in these models.