Browsing by Author "Deepak Chouhan"

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Dermorphin [D-Arg2, Lys4] (1-4) Amide Alleviates Frostbite-Induced Pain by Regulating TRP Channel-Mediated Microglial Activation and Neuroinflammation
(Springer, 2024) Obulapathi Ummadisetty; Akhilesh; Anagha Gadepalli; Deepak Chouhan; Utkarsh Patil; Surya Pratap Singh; Sanjay Singh; Vinod Tiwari
Cold injury or frostbite is a common medical condition that causes serious clinical complications including sensory abnormalities and chronic pain ultimately affecting overall well-being. Opioids are the first-choice drug for the treatment of frostbite-induced chronic pain; however, their notable side effects, including sedation, motor incoordination, respiratory depression, and drug addiction, present substantial obstacle to their clinical utility. To address this challenge, we have exploited peripheral mu-opioid receptors as potential target for the treatment of frostbite-induced chronic pain. In this study, we investigated the effect of dermorphin [D-Arg2, Lys4] (1–4) amide (DALDA), a peripheral mu-opioid receptor agonist, on frostbite injury and hypersensitivity induced by deep freeze magnet exposure in rats. Animals with frostbite injury displayed significant hypersensitivity to mechanical, thermal, and cold stimuli which was significant ameliorated on treatment with different doses of DALDA (1, 3, and 10 mg/kg) and ibuprofen (100 mg/kg). Further, molecular biology investigations unveiled heightened oxido-nitrosative stress, coupled with a notable upregulation in the expression of TRP channels (TRPA1, TRPV1, and TRPM8), glial cell activation, and neuroinflammation (TNF-α, IL-1β) in the sciatic nerve, dorsal root ganglion (DRG), and spinal cord of frostbite-injured rats. Treatment with DALDA leads to substantial reduction in TRP channels, microglial activation, and suppression of the inflammatory cascade in the ipsilateral L4–L5 DRG and spinal cord of rats. Overall, findings from the present study suggest that activation of peripheral mu-opioid receptors mitigates chronic pain in rats by modulating the expression of TRP channels and suppressing glial cell activation and neuroinflammation. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024.
Mechanism and modulation of spontaneous pain: from neural circuits to drug development
(Springer Science and Business Media B.V., 2025) Deepak Chouhan; Akhilesh; Dilip Sharma; Vinod N. Tiwari
Spontaneous pain, a pervasive and debilitating sensation occurring without external stimuli, represents a significant challenge in chronic pain management. Despite substantial advancements in the understanding of pain pathophysiology, current therapeutic strategies fail to adequately address spontaneous pain, contributing to the ongoing gap between preclinical findings and clinical outcomes. Historically, drug discovery has predominantly focused on the mechanisms underlying evoked pain, neglecting the unique neurobiology of spontaneous pain. This narrow focus has hindered progress in developing effective treatments. Emerging evidence from pharmacological and optogenetic studies underscores the involvement of sensory afferent fibers, descending pain pathways, cortical circuits, and thalamic and subthalamic nuclei in spontaneous pain processing. This review comprehensively explores the neurobiology of spontaneous pain, emphasizing the roles of these neural pathways and identifying novel druggable targets. Additionally, we examine the clinical implications of these findings and propose strategies to bridge the translational gap. To foster the development of innovative and effective pain therapies, we advocate for a paradigm shift in preclinical research that prioritizes robust assessments of spontaneous pain mechanisms. By aligning preclinical models with clinical symptomatology, we aim to advance the understanding and treatment of this underappreciated yet critical dimension of chronic pain. © The Author(s), under exclusive licence to Springer Nature B.V. 2025.
Multifarious Targets and Recent Developments in the Therapeutics for the Management of Bone Cancer Pain
(American Chemical Society, 2021) Anagha Gadepalli; Akhilesh; Ankit Uniyal; Ajay Modi; Deepak Chouhan; Obulapathi Ummadisetty; Shreya Khanna; Shreya Solanki; Meghana Allani; Vinod Tiwari
Bone cancer pain (BCP) is a distinct pain state showing characteristics of both neuropathic and inflammatory pain. On average, almost 46% of cancer patients exhibit BCP with numbers flaring up to as high as 76% for terminally ill patients. Patients suffering from BCP experience a compromised quality of life, and the unavailability of effective therapeutics makes this a more devastating condition. In every individual cancer patient, the pain is driven by different mechanisms at different sites. The mechanisms behind the manifestation of BCP are very complex and poorly understood, which creates a substantial barrier to drug development. Nevertheless, some of the key mechanisms involved have been identified and are being explored further to develop targeted molecules. Developing a multitarget approach might be beneficial in this case as the underlying mechanism is not fixed and usually a number of these pathways are simultaneously dysregulated. In this review, we have discussed the role of recently identified novel modulators and mechanisms involved in the development of BCP. They include ion channels and receptors involved in sensing alteration of temperature and acidic microenvironment, immune system activation, sodium channels, endothelins, protease-activated receptors, neurotrophins, motor proteins mediated trafficking of glutamate receptor, and some bone-specific mechanisms. Apart from this, we have also discussed some of the novel approaches under preclinical and clinical development for the treatment of bone cancer pain. © 2021 American Chemical Society.
Unlocking the potential of TRPV1 based siRNA therapeutics for the treatment of chemotherapy-induced neuropathic pain
(Elsevier Inc., 2022) Akhilesh; Ankit Uniyal; Anagha Gadepalli; Vineeta Tiwari; Meghana Allani; Deepak Chouhan; Obulapathi Ummadisetty; Nimisha Verma; Vinod Tiwari
Chemotherapy-induced neuropathic pain (CINP) is among the most common clinical complications associated with the use of anti-cancer drugs. CINP occurs in nearly 68.1% of the cancer patients receiving chemotherapeutic drugs. Most of the clinically available analgesics are ineffective in the case of CINP patients as the pathological mechanisms involved with different chemotherapeutic drugs are distinct from each other. CINP triggers the somatosensory nervous system, increases the neuronal firing and activation of nociceptive mediators including transient receptor protein vanilloid 1 (TRPV1). TRPV1 is widely present in the peripheral nociceptive nerve cells and it has been reported that the higher expression of TRPV1 in DRGs serves a critical role in the potentiation of CINP. The therapeutic glory of TRPV1 is well recognized in clinics which gives a promising insight into the treatment of pain. But the adverse effects associated with some of the antagonists directed the scientists towards RNA interference (RNAi), a tool to silence gene expression. Thus, ongoing research is focused on developing small interfering RNA (siRNA)-based therapeutics targeting TRPV1. In this review, we have discussed the involvement of TRPV1 in the nociceptive signaling associated with CINP and targeting this nociceptor, using siRNA will potentially arm us with effective therapeutic interventions for the clinical management of CINP. © 2021 Elsevier Inc.