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Ambroxol is a multifaceted drug with primarily mucoactive and secretolytic actions, along with anti-inflammatory, antioxidant, and local anaesthetic properties. It has a long history of use in the treatment of respiratory tract diseases and has shown to be efficacious in relieving sore throat. In more recent years, ambroxol has gained interest for its potential usefulness in treating neuropathic pain. Research into this area has been slow, despite clear preclinical evidence to support its primary analgesic mechanism of action – blockade of voltage-gated sodium (Nav) channels in sensory neurons. Ambroxol is a commercially available inhibitor of Nav1.8, a crucial player in the pathophysiology of neuropathic pain, and Nav1.7, a particularly exciting target for the treatment of chronic pain. In this review, we discuss the analgesic mechanisms of action of ambroxol, as well as proposed synergistic properties, followed by the preclinical and clinical results of its use in the treatment of persistent pain and neuropathic pain symptoms, including trigeminal neuralgia, fibromyalgia, and complex regional pain syndrome. With its well-established safety profile, extensive preclinical and clinical drug data, and early evidence of clinical effectiveness, ambroxol is an old drug worthy of further investigation for repurposing. As a patent-expired drug, a push is needed to progress the drug to clinical trials for neuropathic pain. We encourage the pharmaceutical industry to look at patented drug formulations and take an active role in bringing an optimized version for neuropathic pain to market.
Learn More >It is becoming increasingly clear that robust sex differences exist in the processing of acute and chronic pain in both rodents and humans. However, the underlying mechanism has not been well characterized. The dorsal horn of the lumbar spinal cord is the fundamental building block of ascending and descending pain pathways. It has been shown that numerous neurotransmitter and neuromodulator systems in the spinal cord, including the endocannabinoid system and its main receptor, the cannabinoid 1 receptor (CB R), play vital roles in processing nociceptive information. Our previous findings have shown that CB R mRNA is widely expressed in the brain in sex-dependent patterns. However, the sex-, lamina-, and cell-type-specific characteristics of CB R expression in the spinal cord have not been fully described. In this study, the CB R-iCre-EGFP mouse strain was generated to label and identify CB R-positive (CB R ) cells. We reported no sex difference in CB R expression in the lumbar dorsal horn of the spinal cord, but a dynamic distribution within superficial laminae II and III in female mice between estrus and nonestrus phases. Furthermore, the cell-type-specific CB R expression pattern in the dorsal horn was similar in both sexes. Over 50% of CB R cells were GABAergic neurons, and approximately 25% were glycinergic and 20-30% were glutamatergic neurons. The CB R-expressing cells also represented a subset of spinal projection neurons. Overall, our work indicates a highly consistent distribution pattern of CB R cells in the dorsal horn of lumbar spinal cord in males and females.
Learn More >The encoding of noxious stimuli into action potential firing is largely mediated by nociceptive free nerve endings. Tissue inflammation, by changing the intrinsic properties of the nociceptive endings, leads to nociceptive hyperexcitability, and thus to the development of inflammatory pain. Here, we showed that tissue inflammation-induced activation of the mammalian target of rapamycin complex 2 (mTORC2) triggers changes in the architecture of nociceptive terminals and leads to inflammatory pain. Pharmacological activation of mTORC2 induced elongation and branching of nociceptor peripheral endings and caused long-lasting pain hypersensitivity. Conversely, nociceptor-specific deletion of the mTORC2 regulatory protein, Rictor, prevented inflammation-induced elongation and branching of cutaneous nociceptive fibers and attenuated inflammatory pain hypersensitivity. Computational modelling demonstrated that mTORC2-mediated structural changes in the nociceptive terminal tree are sufficient to increase the excitability of nociceptors. Targeting mTORC2 using a single injection of antisense oligonucleotide against Rictor provided long-lasting alleviation of inflammatory pain hypersensitivity. Collectively, we showed that tissue inflammation-induced activation of mTORC2 causes structural plasticity of nociceptive free nerve endings in the epidermis and inflammatory hyperalgesia, representing a therapeutic target for inflammatory pain.
Learn More >BmK DKK13 (DKK13) is a mutated recombinant peptide, which has a significant antinociception in a rat model of the inflammatory pain. The purpose of this study was to evaluate the antinociceptive effect of DKK13 on trigeminal neuralgia (TN) in rats. Male Sprague-Dawley (SD) rats were treated with the chronic constriction injury of the infraorbital nerve (IoN-CCI) model to induce stable symptoms of TN. DKK13 (1.0 mg/kg, 2.0 mg/kg and 4.0 mg/kg, i.v.) or morphine (4.0 mg/kg, i.v.) was administered by tail vein once on day 14 after IoN-CCI injury. Behavioral tests, electrophysiology and western blotting were performed to investigate the role and underlying mechanisms of DKK13 on IoN-CCI model. Behavioral test results showed that DKK13 could significantly increase the mechanical pain and thermal radiation pain thresholds of IoN-CCI rats and inhibit the asymmetric spontaneous pain scratching behavior. Electrophysiological results showed that DKK13 could significantly reduce the current density of Nav1.8 in the ipsilateral side of trigeminal ganglion (TG) neurons in IoN-CCI rats, and the steady-state activation and inactivation curves of Nav1.8 shifted, respectively, to the direction of hyperpolarization and depolarization. Western blotting results showed that DKK13 significantly reduced the expression of Nav1.8 and the phosphorylation levels of key proteins of MAPKs/CREB pathway in TG tissues of IoN-CCI rats. In brief, DKK13 has a significant antinociceptive effect on IoN-CCI rats, which may be achieved by changing the dynamic characteristics of Nav1.8 channel and regulating the protein phosphorylation in MAPKs/CREB pathway.
Learn More >Developing effective strategies to manage perioperative pain remains a focus of cleft care. The present study's purpose was to systematically review perioperative pain control strategies for cleft lip and palate repair.
Learn More >Chronic pruritus is one of the most common conditions in dermatology as well as a common manifestation in many systemic diseases. Since the etiology of chronic pruritus remains somewhat unknown, hence, conventional medications may not always show a good therapeutic response. This finding has led both investigators and patients to use herbal and complementary remedies for its treatment. The aim of this study was to review clinical trials in which herbal and complementary medicine was used in the control and treatment of chronic pruritus.
Learn More >Pain is commonly reported in people living with myositis. This study assesses the presence of pain in the subtypes of myositis as well frequency of opioid and non-opioid pain medication use.
Learn More >SignificanceNeuropathic pain affects nearly 10% of the US population, and yet current treatments with small-molecule drugs fail to adequately alleviate nociception and often produce serious side effects. High-voltage-activated calcium channels (HVACCs) are membrane proteins that are necessary for synaptic transmission in sensory neurons, and inhibiting these channels is a proven method to achieve analgesia. In this work, we used subcutaneous injection to express a genetically encoded molecule that blocks HVACCs in sensory neurons in vivo. We demonstrate that this approach effectively reduces the onset of neuropathic pain in an animal model of the disease without any observable side effects. These studies support the development of a gene therapy targeting the inhibition of HVACCs to preempt, and potentially reverse, neuropathic pain.
Learn More >In recent years, extracorporeal shock wave therapy (ESWT) has received increasing attention for its potential beneficial effects on various bone and soft-tissue pathologies, yielding promising outcomes for pain relief and functional recovery. In fact, ESWT has emerged as an alternative, non-invasive, and safe treatment for the management of numerous musculoskeletal disorders, including myofascial pain syndrome (MPS). In particular, MPS is a common chronic painful condition, accounting for the largest proportion of patients affected by musculoskeletal problems. Remarkably, sensory innervation and nociceptors of the fascial system are emerging to play a pivotal role as pain generators in MPS. At the same time, increasing evidence demonstrates that application of ESWT results in selective loss of sensory unmyelinated nerve fibers, thereby inducing long-lasting analgesia. The findings discussed in the present review are supposed to add novel viewpoints that may further enrich our knowledge on the complex interactions occurring between disorders of the deep fascia including changes in innervation, sensitization of fascial nociceptors, the pathophysiology of chronic musculoskeletal pain of MPS, and EWST-induced analgesia. Moreover, gaining mechanistic insights into the molecular mechanisms of pain-alleviating effects of ESWT may broaden the fields of shock waves clinical practice far beyond the musculoskeletal system or its original application for lithotripsy.
Learn More >Neuropathic pain is a challenging complaint for patients and clinicians since there are no effective agents available to get satisfactory outcomes even though the pharmacological agents target reasonable pathophysiological mechanisms. This may indicate that other aspects in these mechanisms should be unveiled to comprehend the pathogenesis of neuropathic pain and thus find more effective treatments. Therefore, in the present study, several mechanisms are chosen to be reconsidered in the pathophysiology of neuropathic pain from a quantum mechanical perspective. The mathematical model of the ions quantum tunneling model is used to provide quantum aspects in the pathophysiology of neuropathic pain. Three major pathophysiological mechanisms are revisited in the context of the quantum tunneling model. These include: (1) the depolarized membrane potential of neurons; (2) the cross-talk or the ephaptic coupling between the neurons; and (3) the spontaneous neuronal activity and the emergence of ectopic action potentials. We will show mathematically that the quantum tunneling model can predict the occurrence of neuronal membrane depolarization attributed to the quantum tunneling current of sodium ions. Moreover, the probability of inducing an ectopic action potential in the axons of neurons will be calculated and will be shown to be significant and influential. These ectopic action potentials are generated due to the formation of quantum synapses which are assumed to be the mechanism behind the ephaptic transmission. Furthermore, the spontaneous neuronal activity and the emergence of ectopic action potentials independently from any adjacent stimulated neurons are predicted to occur according to the quantum tunneling model. All these quantum mechanical aspects contribute to the overall hyperexcitability of the neurons and to the pathogenesis of neuropathic pain. Additionally, providing a new perspective in the pathophysiology of neuropathic pain may improve our understanding of how the neuropathic pain is generated and maintained and may offer new effective agents that can improve the overall clinical outcomes of the patients.
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