Plasticity In Spinal Dorsal Horn Research Articles

Analgesic Effect of Perineural Injection of BoNT/A on Neuropathic Pain Induced by Chronic Constriction Injury of Sciatic Nerve in Rats.

This study was designed to investigate the analgesic effect of perineural injection of BoNT/A on neuropathic pain induced by sciatic nerve chronic constriction injury (CCI) and possible mechanisms. SD rats were randomly divided into Sham group, CCI group and BoNT/A group. Paw mechanical withdrawal threshold (pMWT) and paw thermal withdrawal latency (pTWL) of each group were detected at different time points after surgery. The expression of myelin markers, autophagy markers and NLRP3 inflammasome-related molecules in injured sciatic nerves were examined at 12days after surgery. Moreover, C-fiber evoked potential in spinal dorsal horn was recorded. The expression of SNAP-25, neuroinflammation and synaptic plasticity in spinal dorsal horn of each group were examined. Then rats treated with BoNT/A were randomly divided into DMSO group and Wnt agonist group to further explore the regulatory effect of BoNT/A on Wnt pathway. We found that pMWT and pTWL of ipsilateral paw were significantly decreased in CCI group compared with Sham group, which could be improved by perineural injection of BoNT/A at days 7, 9 and 12 after surgery. The peripheral analgesic mechanisms of perineural injection of BoNT/A might be related to the protective effect on myelin sheath by inhibiting NLRP3 inflammasome and promoting autophagy flow, while the central analgesic mechanisms might be associated with inhibition of neuroinflammation and synaptic plasticity in spinal dorsal horn due to inhibiting SNAP-25 and Wnt pathway. As a new route of administration, perineural injection of BoNT/A can relieve CCI induced neuropathic pain probablyvia both peripheral andcentral analgesic mechanisms.

Normalization of Neuroinflammation: A New Strategy for Treatment of Persistent Pain and Memory/Emotional Deficits in Chronic Pain.

Chronic pain, which affects around 1/3 of the world population and is often comorbid with memory deficit and mood depression, is a leading source of suffering and disability. Studies in past decades have shown that hyperexcitability of primary sensory neurons resulting from abnormal expression of ion channels and central sensitization mediated pathological synaptic plasticity, such as long-term potentiation in spinal dorsal horn, underlie the persistent pain. The memory/emotional deficits are associated with impaired synaptic connectivity in hippocampus. Dysregulation of numerous endogenous proteins including receptors and intracellular signaling molecules is involved in the pathological processes. However, increasing knowledge contributes little to clinical treatment. Emerging evidence has demonstrated that the neuroinflammation, characterized by overproduction of pro-inflammatory cytokines and glial activation, is reliably detected in humans and animals with chronic pain, and is sufficient to induce persistent pain and memory/emotional deficits. The abnormal expression of ion channels and pathological synaptic plasticity in spinal dorsal horn and in hippocampus are resulting from neuroinflammation. The neuroinflammation is initiated and maintained by the interactions of circulating monocytes, glial cells and neurons. Obviously, unlike infectious diseases and cancer, which are caused by pathogens or malignant cells, chronic pain is resulting from alterations of cells and molecules which have numerous physiological functions. Therefore, normalization (counterbalance) but not simple inhibition of the neuroinflammation is the right strategy for treating neuronal disorders. Currently, no such agent is available in clinic. While experimental studies have demonstrated that intracellular Mg2+ deficiency is a common feature of chronic pain in animal models and supplement Mg2+ are capable of normalizing the neuroinflammation, activation of upregulated proteins that promote recovery, such as translocator protein (18k Da) or liver X receptors, has a similar effect. In this article, relevant experimental and clinical evidence is reviewed and discussed.

Inhibition of α5 subunit-containing GABAA receptors facilitated spinal nociceptive transmission and plasticity.

γ-Aminobutyric acid (GABA) type A receptors (GABAA Rs) locate at both synaptic and extrasynaptic membrane, which generate phasic and tonic inhibition, respectively. In spinal cord dorsal horn, the phasic inhibition produced by transient activation of synaptic GABAA Rs plays an important role in the gating control over nociceptive conveyance. Although extrasynaptic GABAA Rs that contain α5 subunits (α5-GABAA Rs) are also detectable in spinal dorsal horn, much less is known about the function of these receptors. The C fibre-evoked field potentials were recorded in superficial dorsal horn of spinal cord, and the effects of α5-GABAA R inverse agonist L-655708 on basal synaptic transmission and long-term potentiation (LTP) of C-fibre responses were examined. The possible changes of glutamate receptor function and pain sensitivity after α5-GABAA R inhibition were investigated by western blot and behavioural tests. Inhibition of α5-GABAA Rs by L-655708 boosted the basal synaptic transmission and facilitated the induction of N-methyl-d-aspartate subtype glutamate receptors (NMDARs)-dependent LTP. L-655708 was found to enhance the phosphorylation and synaptic accumulation of NMDARs and α-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid receptors (AMPARs). Intrathecal L-655708 injection also decreased the pain thresholds of intact mice in a dose-dependent manner. α5-GABAA Rs were critical for the tonic inhibition of glutamatergic neurotransmission and plasticity in spinal dorsal horn. Tonic inhibition generated by α5-GABAA Rs is important for information processing. However, whether and how α5-GABAA Rs regulate the conveyance of nociceptive signals in spinal cord is largely unknown. Here, we revealed a negative control by α5-GABAA Rs over nociceptive transmission and plasticity.

Interleukin-1β Induces Long-Term Potentiation of C-Fiber Evoked Field Potentials in Spinal dorsal Horn in Rats with Neuropathic Pain

Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β), impairs long-term potentiation (LTP) in hippocampus, a synaptic model of memory, while in spinal dorsal horn TNF-α is found to induce LTP of C-fiber evoked field potentials in rats with nerve injury. In the present work the role of IL-1β in the spinal LTP of C-fiber evoked field potentials, which is important for pathological pain, was investigated in both physiological and pathological conditions. We found that spinal application of IL-1β at the concentrations up to 500 ng/ml affected neither basal synaptic transmission mediated by C-fiber nor spinal LTP induced by tetanic stimulation in intact rats. In rats with neuropathic pain produced by spared nerve injury (SNI) or lumbar 5 ventral root transection (L5 VRT), however, IL- 1β at a low concentration (5 ng/ml) induced LTP of C-fiber evoked field potentials. Pretreatment with either p38 MAPK inhibitor (SB203580) or NF-κB inhibitor (PDTC) but not with JNK inhibitor (SP600125) completely blocked LTP induced by IL-1β in SNI rats. Taken together, the results indicated that exogenous IL-1β might induce spinal LTP only in rats with nerve injury but not in intact rats. The differential effects of proinflammatory cytokines on synaptic plasticity in spinal dorsal horn and in hippocampus may be clinically significant.

Incorporating synaptic time-dependent plasticity and dynamic synapse into a computational model of wind-up

Wind-up, a condition related to chronic pain, is a form of plasticity in spinal dorsal horn that can be observed during electrical stimulation of pain receptors at low frequencies (0.3-3 Hz). In ...

Incorporating synaptic time-dependent plasticity and dynamic synapse into a computational model of wind-up

"Wind-up", a condition related to chronic pain, is a form of plasticity in spinal dorsal horn that can be observed during electrical stimulation of pain receptors at low frequencies (0.3-3 Hz). In this paper, we present a computational model to explain several aspects of wind-up. The core of this model is the interplay of spike-time-dependent plasticity (STDP), short-term synaptic plasticity (STP), and different propagation velocities of the three afferent fibers (C, Adelta, and Abeta). We utilize Izhikevich's simple spiking neuron to model a dorsal horn neuron (DHN) of the spinal cord. To achieve the expected results, the model parameters need to adapt to the frequency response which is motivated by biological results. The adaptation is performed by a genetic algorithm (GA), and the resulting optimized values interestingly lie in biological ranges. Based on the proposed model, we suggest that STP may be the origin of the band-pass behavior of wind-up between 0.3 and 3 Hz; while the STDP-based long-term plasticity can be responsible for the synaptic potentiation leading to wind-up, or similar phenomena such as central sensitization. Understanding the mechanisms underlying wind-up generation might allow clarification of the molecular mechanisms of pain signaling and development of strategies, such as transcutaneous electrical nerve stimulation (TENS), for pain treatment.

Clonidine depresses LTP of C-fiber evoked field potentials in spinal dorsal horn via NO-cGMP pathway

Clonidine, a specific α 2-adrenergic receptor agonist, has been found to be effective for the treatment of neuropathic pain, the mechanism underlying the effect is, however, not well understood. Here, the effect of clonidine on long-term potentiation (LTP) of C-fiber evoked field potentials in spinal dorsal horn, which is a synaptic model of injury-induced hyperalgesia, was investigated. LTP of C-fiber evoked field potentials was recorded in the superficial layers of spinal dorsal horn in anesthetized adult Sprague–Dawley rats. Clonidine and other substances were applied locally at the recording spinal segments before or after LTP induction by tetanic stimulation. We found that (1) Clonidine completely blocked LTP induction, when applied 30 min before tetanic stimulation and depressed spinal LTP, when applied 30 min and 3 h after LTP induction. (2) The inhibitory effect of clonidine on spinal LTP had two phases: a fast phase lasting for about 3.5 h and a slow phase persisting for the rest time of experiments (up to 8 h after drug). (3) Spinal clonidine at low dose (10.7 μg/100 μl) depressed spinal LTP but not C-fiber baseline response and at higher dose (107 μg/100 μl) depressed both of them. (4) Pretreatment with α2-adrenergic receptor antagonist yohimbine completely blocked the inhibitory effect of clonidine. (5) Pretreatment with muscarinic receptor antagonist atropine, nitric oxide synthesis inhibitor l-NNA or cGMP inhibitor ODQ depressed the fast phase inhibition significantly and abolished the slow phase inhibition completely. These results suggest that clonidine may exert analgesic effect by depressing the synaptic plasticity in spinal dorsal horn, via activation of muscarinic receptor-NO-cGMP pathway.