Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores

Based on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist, and the second pharmacophore is an antagonist of the pronociceptive system, i.e., an antagonist of the melanocortin-4 receptor. The results of tests in acute and neuropathic pain models of the obtained compounds have shown that the type of linker used to connect pharmacophores had an effect on antinociceptive activity. Peptidomimetics containing longer flexible linkers were very effective at low doses in the neuropathic pain model. To elucidate the effect of linker lengths, two hybrids showing very high activity and two hybrids with lower activity were further tested for affinity for opioid (mu, delta) and melanocortin-4 receptors. Their complexes with the target receptors were also studied by molecular modelling. Our results do not show a simple relationship between linker length and affinity for particular receptor types but suggest that activity in neuropathic pain is related to a proper balance of receptor affinity rather than maximum binding to any or all of the target receptors.

Antinociceptive Effects of Aza-Bicyclic Isoxazoline-Acylhydrazone Derivatives in Different Models of Nociception in Mice

Background: In a study recently published by our research group, the compounds isoxazoline-acylhydrazone derivatives R-99 and R-123 presented promising antinociceptive activity. However, the mechanism of action of this compound is still unknown. Objective: This study aimed to assess the mechanisms involved in the antinociceptive activity of these compounds in chemical models of pain. Methods: Animals were orally pretreated and evaluated in the acetic acid-, formalin-, capsaicin-, carrageenan- and Complete Freund's Adjuvant (CFA)-induced pain models in mice. The effects of the compounds after pretreatment with naloxone, prazosin, yohimbine, atropine, L-arginine, or glibenclamide were studied, using the acetic acid-induced writhing test to verify the possible involvement of opioid, α1-adrenergic, α2-adrenergic or cholinergic receptors, and nitric oxide or potassium channels pathways, respectively. Results: R-99 and R-123 compounds showed significant antinociceptive activity on pain models induced by acetic acid, formalin, and capsaicin. Both compounds decreased the mechanical hyperalgesia induced by carrageenan or CFA in mice. The antinociceptive effects of R-99 and R-123 on the acetic acid-induced writhing test were significantly attenuated by pretreatment with naloxone, yohimbine or atropine. R-99 also showed an attenuated response after pretreatment with atropine and glibenclamide. However, on the pretreatment with prazosin, there was no change in the animals' response to both compounds. Conclusion: R-99 and R-123 showed antinociceptive effects related to mechanisms that involve, at least in part, interaction with the opioid and adrenergic systems and TRPV1 pathways. The compound R-99 also interacts with the cholinergic pathways and potassium channels.

Differential Rearrangement of Excitatory Inputs to the Medial Prefrontal Cortex in Chronic Pain Models

Chronic pain patients suffer a disrupted quality of life not only from the experience of pain itself, but also from comorbid symptoms such as depression, anxiety, cognitive impairment, and sleep disturbances. The heterogeneity of these symptoms support the idea of a major involvement of the cerebral cortex in the chronic pain condition. Accordingly, abundant evidence shows that in chronic pain the activity of the medial prefrontal cortex (mPFC), a brain region that is critical for executive function and working memory, is severely impaired. Excitability of the mPFC depends on the integrated effects of intrinsic excitability and excitatory and inhibitory inputs. The main extracortical sources of excitatory input to the mPFC originate in the thalamus, hippocampus, and amygdala, which allow the mPFC to integrate multiple information streams necessary for cognitive control of pain including sensory information, context, and emotional salience. Recent techniques, such as optogenetic methods of circuit dissection, have made it possible to tease apart the contributions of individual circuit components. Here we review the synaptic properties of these main glutamatergic inputs to the rodent mPFC, how each is altered in animal models of chronic pain, and how these alterations contribute to pain-associated mPFC deactivation. By understanding the contributions of these individual circuit components, we strive to understand the broad spectrum of chronic pain and comorbid pathologies, how they are generated, and how they might be alleviated.

Roles of Long Non-coding RNAs in the Development of Chronic Pain

Chronic pain, a severe public health issue, affects the quality of life of patients and results in a major socioeconomic burden. Only limited drug treatments for chronic pain are available, and they have insufficient efficacy. Recent studies have found that the expression of long non-coding RNAs (lncRNAs) is dysregulated in various chronic pain models, including chronic neuropathic pain, chronic inflammatory pain, and chronic cancer-related pain. Studies have also explored the effect of these dysregulated lncRNAs on the activation of microRNAs, inflammatory cytokines, and so on. These mechanisms have been widely demonstrated to play a critical role in the development of chronic pain. The findings of these studies indicate the significant roles of dysregulated lncRNAs in chronic pain in the dorsal root ganglion and spinal cord, following peripheral or central nerve lesions. This review summarizes the mechanism underlying the abnormal expression of lncRNAs in the development of chronic pain induced by peripheral nerve injury, diabetic neuropathy, inflammatory response, trigeminal neuralgia, spinal cord injury, cancer metastasis, and other conditions. Understanding the effect of lncRNAs may provide a novel insight that targeting lncRNAs could be a potential candidate for therapeutic intervention in chronic pain.

Asprosin, a Novel Therapeutic Candidate for Painful Neuropathy: An Experimental Study in Mice

Neuropathic pain is primarily caused by nervous system lesions or dysfunction. Evidence strongly suggests that obesity, diabetes and cancer are common in chronic pain conditions, and pain complaints are common in these individuals. Recent studies indicate presence of a strong link between adipokines and neuropathic pain. However, the effects of asprosin, a novel adipokine, on neuropathic pain have not been studied in animal modelsMouse models were employed to investigate the antinociceptive effectiveness of asprosin in the treatment of three types of neuropathic pain, with metabolic (streptozocin/STZ), toxic (oxaliplatin/OXA), and traumatic (sciatic nerve ligation/CCI [chronic constriction nerve injury]) etiologies, respectively. Changes in nociceptive behaviors were assessed relative to controls using thermal (the hot plate and cold plate tests, at 50 °C and 4 °C respectively) and mechanical pain (Von Frey test) tests at baseline and 30, 60, 120 and 180 minutes after asprosin administration. Serum level of asprosin was quantified by ELISA. In all three neuropathic pain models (STZ, OXA and CCI), asprosin administration significantly reduced both mechanical and thermal hypersensitivity, indicating that it exhibits a clear-cut antihypersensitivity effect in the analyzed neuropathic pain models. Asprosin levels were significantly lower in three types of neuropathic pain compare to controls (p < 0.05). The results yielded by the present study suggest that asprosin exhibits an analgesic effect in the neuropathic pain models and may have clinical utility in alleviating chronic pain associated with disease and injury originating from peripheral structures.

Cav3.2 calcium channels involvement in inflammation and related pain-like symptoms in murine inflammatory models

Background and Purpose T-type calcium channels, mainly the Cav3.2 subtype, are important contributors to the nociceptive signaling pathway. We investigated their involvement in inflammation and related pain-like symptoms. Experimental Approach The involvement of Cav3.2 and T-type channels was investigated using genetic and pharmacological inhibition to assess mechanical allodynia/hyperalgesia and edema development in two murine inflammatory pain models. The location of Cav3.2 involved in pain-like symptoms was studied in mice with Cav3.2 knocked out in C-low threshold mechanoreceptors (C-LTMR) and the use of ABT-639, a peripherally restricted T-type channel inhibitor. The anti-edematous effect of Cav3.2 inhibition was investigated in chimeric mice with immune cells deleted for Cav3.2. Lymphocytes and macrophages from either green fluorescent protein-targeted Cav3.2 or KO mice were used to determine the expression of Cav3.2 protein and the functional status of the cells. Key Results We showed the role of Cav3.2 channels in the development of pain-like symptoms and edema in the two murine inflammatory pain models. For the first time, we provide evidence of the involvement of Cav3.2 channels located on C-LTMRs in inflammatory pain at both peripheral and primary afferent terminals at the spinal level. We showed that Cav3.2 channels located in T cells and macrophages contribute to the inflammatory process. Conclusion and Implications This work highlights the crucial role of Cav3.2 channels in inflammation and related pain and suggests that targeting Cav3.2 channels with pharmacological agents could be an attractive and readily evaluable strategy in a clinical trial to relieve chronic inflammatory pain in affected patients.

Understanding the Mechanism of Action of NAI-112, a Lanthipeptide with Potent Antinociceptive Activity

NAI-112, a glycosylated, labionine-containing lanthipeptide with weak antibacterial activity, has demonstrated analgesic activity in relevant mouse models of nociceptive and neuropathic pain. However, the mechanism(s) through which NAI-112 exerts its analgesic and antibacterial activities is not known. In this study, we analyzed changes in the spinal cord lipidome resulting from treatment with NAI-112 of naive and in-pain mice. Notably, NAI-112 led to an increase in phosphatidic acid levels in both no-pain and pain models and to a decrease in lysophosphatidic acid levels in the pain model only. We also showed that NAI-112 can form complexes with dipalmitoyl-phosphatidic acid and that Staphylococcus aureus can become resistant to NAI-112 through serial passages at sub-inhibitory concentrations of the compound. The resulting resistant mutants were phenotypically and genotypically related to vancomycin-insensitive S. aureus strains, suggesting that NAI-112 binds to the peptidoglycan intermediate lipid II. Altogether, our results suggest that NAI-112 binds to phosphate-containing lipids and blocks pain sensation by decreasing levels of lysophosphatidic acid in the TRPV1 pathway.