Human birth tissue products as a regenerative medicine to inhibit post-surgical pain through multi-modal action.

Pain after surgery causes significant suffering. Opioid analgesics cause severe side effects and accidental death. Therefore, there is an urgent need to develop non-opioid therapies for managing post-surgical pain and, more importantly, preventing its transition to a chronic state. In a mouse model of post-surgical pain, local application of Clarix Flo (FLO), a human amniotic membrane (AM) product, attenuated established post-surgical pain hypersensitivity without exhibiting known side effects of opioid use in mice. Importantly, preemptive drug treatment also inhibited the transition of post-surgical pain to a prolonged state. This effect was achieved through direct inhibition of nociceptive dorsal root ganglion (DRG) neurons via CD44-dependent pathways, and indirect pain relief by attenuating immune cell recruitment. We further purified the major matrix component, the heavy chain-hyaluronic acid/pentraxin 3 (HC-HA/PTX3) from human AM that has greater purity and water solubility than FLO. HC-HA/PTX3 replicated FLO-induced neuronal and pain inhibition. Mechanistically, HC-HA/PTX3 induced cytoskeleton rearrangements to inhibit sodium current and high-voltage activated calcium current on nociceptive neurons, suggesting it is a key bioactive component mediating pain relief. Collectively, our findings highlight the potential of naturally derived biologics from human birth tissues as an effective non-opioid treatment for post-surgical pain and unravel the underlying mechanisms.

Open and Percutaneous Trigeminal Nucleotractotomy: A Case Series and Literature Review.

INTRODUCTION: Nucleotractotomy is an efficient surgical technique that provides a high pain relief rate for specific clinical indications. There are two main approaches for performing this operation: an open and percutaneous technique. METHODS: In the Federal Center of Neurosurgery (Novosibirsk, Russia) from 2016 to 2022, 13 trigeminal nucleotractotomies (7 open and 6 percutaneous) were performed in 12 patients (5 women and 7 men). The indications for surgery were deafferentation pain and chronic drug-resistant pain syndrome caused by malignancy in the facial region. A neurological examination was done on each patient 1 day before the surgery, right after the surgery, and at the follow-up (examinations were done after 1, 6, and 12 months, or when the patient independently applied to our hospital). In the early postoperative period, patients underwent brain MRI. RESULTS: The average pain intensity score before nucleotractotomy on the 11-point (0-10) visual analog scale (VAS) was 9.3. The effectiveness of open interventions was somewhat higher; the average VAS score in the early postoperative period for the open technique was 1.57, in the group of patients who underwent percutaneous nucleotractotomy were 2.66. Complete regression of the pain syndrome was achieved in 6 patients; in 5 patients, the pain in the face decreased by more than 50%. One case had an unsatisfactory outcome. In the open-surgery group in the early postoperative period, according to MRI, the average length of the visualized area of signal change was longer (21.5 mm, the average diameter was 3.75 mm) than in a percutaneous nucleotractotomy group (16 mm, the average diameter was 3.75 mm). During the postoperative period (average follow-up 40 months), the pain recurred in 3 patients (30%): 2 patients after percutaneous nucleotractotomy (3 and 18 months after surgery) and in 1 patient 4 months after the open surgery. The mean VAS score at the last follow-up was 2.6. CONCLUSION: Trigeminal nucleotractotomy is an effective approach to the treatment of intractable facial pain. Our experience suggests this technique is highly effective in patients with drug-resistant pain caused by craniofacial tumors and deafferentation conditions after treating trigeminal neuralgia.

Current Evidence for Biological Biomarkers and Mechanisms Underlying Acute to Chronic Pain Transition across the Pediatric Age Spectrum.

Chronic pain is highly prevalent in the pediatric population. Many factors are involved in the transition from acute to chronic pain. Currently, there are conceptual models proposed, but they lack a mechanistically sound integrated theory considering the stages of child development. Objective biomarkers are critically needed for the diagnosis, risk stratification, and prognosis of the pathological stages of pain chronification. In this article, we summarize the current evidence on mechanisms and biomarkers of acute to chronic pain transitions in infants and children through the developmental lens. The goal is to identify gaps and outline future directions for basic and clinical research toward a developmentally informed theory of pain chronification in the pediatric population. At the outset, the importance of objective biomarkers for chronification of pain in children is outlined, followed by a summary of the current evidence on the mechanisms of acute to chronic pain transition in adults, in order to contrast with the developmental mechanisms of pain chronification in the pediatric population. Evidence is presented to show that chronic pain may have its origin from insults early in life, which prime the child for the development of chronic pain in later life. Furthermore, available genetic, epigenetic, psychophysical, electrophysiological, neuroimaging, neuroimmune, and sex mechanisms are described in infants and older children. In conclusion, future directions are discussed with a focus on research gaps, translational and clinical implications. Utilization of developmental mechanisms framework to inform clinical decision-making and strategies for prevention and management of acute to chronic pain transitions in children, is highlighted.

Steering Toward Normative Wide-Dynamic-Range Neuron Activity in Nerve-Injured Rats With Closed-Loop Peripheral Nerve Stimulation.

OBJECTIVES: Chronic pain is primarily treated with pharmaceuticals, but the effects remain unsatisfactory. A promising alternative therapy is peripheral nerve stimulation (PNS), but it has been associated with suboptimal efficacy because its modulation mechanisms are not clear and the current therapies are primarily open loop (ie, manually adjusting the stimulation parameters). In this study, we developed a proof-of-concept computational modeling as the first step toward implementing closed-loop PNS in future biological studies. When developing new pain therapies, a useful pain biomarker is the wide-dynamic-range (WDR) neuron activity in the dorsal horn. In healthy animals, the WDR neuron activity occurs in a stereotyped manner; however, this response profile can vary widely after nerve injury to create a chronic pain condition. We hypothesized that if injury-induced changes of neuronal response can be normalized to resemble those of a healthy condition, the pathological aspects of pain may be treated while maintaining protective physiological nociception. MATERIALS AND METHODS: Using an in vivo electrophysiology data set of WDR neuron recordings obtained in nerve-injured rats and naïve rats, we constructed sets of linear phenomenologic models of WDR firing rate during windup stimulation for both conditions. Then, we applied robust control systems techniques to identify a closed-loop PNS controller, which can drive the dynamics of WDR neuron response in neuropathic pain model into ranges associated with normal physiological pain. RESULTS: The sets of identified linear models can accurately predict, in silico, nonlinear neural responses to electrical stimulation of the peripheral nerve. In addition, we showed that continuous closed-loop control of PNS can be used to normalize WDR neuron firing responses in three injured cases. CONCLUSIONS: In this proof-of-concept study, we show how tractable, linear mathematical models of pain-related neurotransmission can be used to inform the development of closed-loop PNS. This new application of robust control to neurotechnology may also be expanded and applied across other neuromodulation applications.

Dysregulated expression of neuregulin-1 by cortical pyramidal neurons disrupts synaptic plasticity.

Neuregulin-1 (NRG1) gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated or decreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions in vivo, we generated mouse mutants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal overexpression of cysteine-rich domain (CRD)-NRG1, the major brain isoform, caused unbalanced excitatory-inhibitory neurotransmission, reduced synaptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an "optimal" level of NRG1 signaling balances excitatory and inhibitory neurotransmission in the cortex. Our data provide a potential pathomechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect.