SUMOylation and DeSUMOylation: Tug of War of Pain Signaling.

SUMOylation is a post-translational modification that attaches a small ubiquitin-like modifier (SUMO) group to a target protein via SUMO ligases, while deSUMOylation refers to the removal of this SUMO group by sentrin-specific proteases (SENPs). Although the functions of these processes have been well described in the nucleus, the role of SUMOylation and deSUMOylation in regulating ion channels is emerging as a novel area of study. Despite this, their contributions to pain signaling remain less clear.

Spinal nerve ligation: An experimental model to study neuropathic pain in rats and mice.

Neuropathic pain, defined as the most terrible of all tortures, which a nerve wound may inflict, is a common chronic painful condition caused by gradual damage or dysfunction of the somatosensory nervous system. As with many chronic diseases, neuropathic pain has a profound economic and emotional impact worldwide and represents a major public health issue from a treatment standpoint. This condition involves multiple sensory symptoms including impaired transmission and perception of noxious stimuli, burning, shooting, spontaneous pain, mechanical or thermal allodynia and hyperalgesia.

C-H Functionalization-Enabled 11-Step Semisynthesis of (-)-Veragranine A and Characterization of Synthetic Analogs in Osteoarthritis-related Pain Treatment.

We report an efficient semisynthesis of the cholestane steroidal alkaloid (-)-veragranine A with a 6/6/6/5/6/6 hexacyclic ring system, eight stereocenters, and a unique C12-C23 linkage. Our synthesis features a Schönecker-Baran C-H oxidation at C12, a Suzuki-Miyaura cross-coupling to form the C12-C23 bond, and a hydrogen atom transfer (HAT)-initiated Minisci C-H cyclization to forge the C20-C22 bond with desired stereochemistry at C20. These enabling transformations significantly enhanced the overall synthetic efficiency and delivered (-)-veragranine A in 11 steps and over 200 mg from cheap and readily available dehydroepiandrosterone.

STINGing away the pain: the role of interferon-stimulated genes.

Pain and inflammation are biologically intertwined responses that warn the body of potential danger. In this issue of the JCI, Defaye, Bradaia, and colleagues identified a functional link between inflammation and pain, demonstrating that inflammation-induced activation of stimulator of IFN genes (STING) in dorsal root ganglia nociceptors reduced pain-like behaviors in a rodent model of inflammatory pain. Utilizing mice with a gain-of-function STING mutation, Defaye, Bradaia, and colleagues identified type I IFN regulation of voltage-gated potassium channels as the mechanism of this pain relief.

Estradiol modulates the role of the spinal α-subunit containing GABA receptors in female rats with neuropathic pain.

The purpose of this study was to investigate the mechanisms underlying sex differences in the role of spinal α-subunit containing GABA (αGABA) receptors in rats with neuropathic pain. Intrathecal 2,5-dihydro-7-methoxy-2-(4-methoxyphenyl)-3H-pyrazolo [4,3-c] quinoline-3-one (PZ-II-029, positive allosteric modulator of αGABA receptors) reduced tactile allodynia in female but not in male rats with neuropathic pain. PZ-II-029 was also more effective in females than males in inflammatory and nociplastic pain.

Nociplastic pain mechanisms and toll-like receptors as promising targets for its management.

Nociplastic pain, characterized by abnormal pain processing without an identifiable organic cause, affects a significant portion of the global population. Unfortunately, current pharmacological treatments for this condition often prove ineffective, prompting the need to explore new potential targets for inducing analgesic effects in patients with nociplastic pain. In this context, toll-like receptors (TLRs), known for their role in the immune response to infections, represent promising opportunities for pharmacological intervention because they play a relevant role in both the development and maintenance of pain.

Lateral fluid percussion injury: A rat model of experimental traumatic brain injury.

Traumatic brain injury (TBI) represents one of the leading causes of disability and death worldwide. The annual economic impact of TBI-including direct and indirect costs-is high, particularly impacting low- and middle-income countries. Despite extensive research, a comprehensive understanding of the primary and secondary TBI pathophysiology, followed by the development of promising therapeutic approaches, remains limited.

A peptidomimetic modulator of the Ca2.2 N-type calcium channel for chronic pain.

Transmembrane Ca2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated, clinically relevant pain targets. Clinical block of Ca2.

Spinal alarmin HMGB1 and the activation of TLR4 lead to chronic stress-induced nociceptive hypersensitivity in rodents.

Chronic stress affects millions of people around the world, and it can trigger different behavioral disorders like nociceptive hypersensitivity and anxiety, among others. However, the mechanisms underlaying these chronic stress-induced behavioral disorders have not been yet elucidated. This study was designed to understand the role of high-mobility group box-1 (HMGB1) and toll-like receptor 4 (TLR4) in chronic stress-induced nociceptive hypersensitivity.

Spinal dopaminergic D and D receptors contribute to reserpine-induced fibromyalgia-like pain in rats.

Fibromyalgia is a complex pain syndrome without a precise etiology. Reduced monoamines levels in serum and cerebrospinal fluid in fibromyalgia patients has been reported and could lead to a dysfunction of descending pain modulatory system producing the painful syndrome. This study evaluated the role of D-like dopamine receptors in the reserpine-induced fibromyalgia-like pain model in female Wistar rats.

Targeting hydrogen sulfide and nitric oxide to repair cardiovascular injury after trauma.

The systemic cardiovascular effects of major trauma, especially neurotrauma, contribute to death and permanent disability in trauma patients and treatments are needed to improve outcomes. In some trauma patients, dysfunction of the autonomic nervous system produces a state of adrenergic overstimulation, causing either a sustained elevation in catecholamines (sympathetic storm) or oscillating bursts of paroxysmal sympathetic hyperactivity. Trauma can also activate innate immune responses that release cytokines and damage-associated molecular patterns into the circulation.

Activation of α 6 -containing GABA A receptors induces antinociception under physiological and pathological conditions.

The loss of GABAergic inhibition is a mechanism that underlies neuropathic pain. Therefore, rescuing the GABAergic inhibitory tone through the activation of GABA A receptors is a strategy to reduce neuropathic pain. This study was designed to elucidate the function of the spinal α 6 -containing GABA A receptor in physiological conditions and neuropathic pain in female and male rats.

Exogenous hydrogen sulfide restores CSE and CBS but no 3-MST protein expression in the hypothalamus and brainstem after severe traumatic brain injury.

Hydrogen sulfide (HS) is a gasotransmitter endogenously synthesized by cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), and 3-mercaptopiruvate sulfurtransferase (3-MST) enzymes. HS exogenous administration prevents the development of hemodynamic impairments after traumatic brain injury (TBI). Since the hypothalamus and the brainstem highly regulate the cardiovascular system, this study aimed to evaluate the effect of NaHS subchronic treatment on the changes of HS-sythesizing enzymes in those brain areas after TBI and in physiological conditions.

Sex-dependent antiallodynic effect of α adrenergic receptor agonist tizanidine in rats with experimental neuropathic pain.

The purpose of this study was to investigate the mechanism of antiallodynic effect of tizanidine in neuropathic rats. Spinal nerve ligation reduced withdrawal threshold which was interpreted as tactile allodynia. Increasing doses of tizanidine induced a dose-dependent antiallodynic effect in nerve injured rats.

The role of spinal cord extrasynaptic α GABA receptors in chronic pain.

Chronic pain is an incapacitating condition that affects a large population worldwide. Until now, there is no drug treatment to relieve it. The impairment of GABAergic inhibition mediated by GABA receptors (GABA R) is considered a relevant factor in mediating chronic pain.

Antinociceptive effects of ceftriaxone in formalin-induced nociception.

Ceftriaxone (CFX) is a β-lactam antibiotic with analgesic properties. However, its role in the formalin-induced nociception remains unknown. The purpose of this study was to investigate the antinociceptive effect of CFX in the 1% formalin test in rats.

Blockade of spinal α-GABA receptors differentially reduces reserpine-induced fibromyalgia-type pain in female rats.

The role of spinal α subunit-containing GABA (α-GABA) receptors in chronic pain is controversial. The purpose of this study was to investigate the participation of spinal α-GABA receptors in the reserpine-induced pain model. Reserpine administration induced tactile allodynia and muscle hyperalgesia in female and male rats.