Polymorphisms in FKBP51 are associated with stress-related psychiatric disorders and influence the severity of pain symptoms experienced after trauma. We report that (FK506 binding protein 51) is crucial for full development maintenance long-term states. Indeed, knockout mice, as well mice which silencing restricted to spinal cord, showed reduced hypersensitivity several persistent models rodents. deletion did not compromise detection acute painful stimuli, a critical protective mechanism....

Autophagy is an intracellular membrane trafficking pathway controlling the delivery of cytoplasmic material to lysosomes for degradation. It plays important role in cell homeostasis both normal settings and abnormal, stressful conditions. now recognised that imbalance autophagic process can impact basal functions this has recently been implicated several human diseases, including neurodegeneration cancer. Here, we investigated consequences nerve injury on a commonly used model neuropathic...

Chronic pain presents an enormous personal and economic burden there is urgent need for effective treatments. In a mouse model of chronic neuropathic pain, selective silencing key neurons in spinal signalling networks with botulinum constructs resulted reduction behaviours associated the peripheral nerve. However, to establish clinical relevance it was important know how long this period lasted. Now, we show that neuronal concomitant mechanical thermal hypersensitivity lasts up 120d...

Autophagy is a homeostatic degradative process essential for basal turnover of long-lived proteins and organelles as well removal dysfunctional cellular components. Dysregulation the autophagic machinery has been recently associated to several conditions including neurodegenerative diseases cancer, but only very few studies have investigated its role in pain processing.We previously described autophagy impairment at spinal cord experimental model neuropathic induced by nerve ligation (SNL)....

It is well established that FKBP51 regulates the stress system by modulating sensitivity of glucocorticoid receptor to hormones. Recently, we have demonstrated also drives long-term inflammatory pain states in male mice signalling at spinal cord level. Here, explored potential as a new pharmacological target for treatment persistent across sexes. First, different aetiologies independently sex. Deletion reduced mechanical hypersensitivity seen joint and neuropathic female mice. Furthermore,...

Silencing key neurons with botulinum toxin conjugates exerts long-lasting pain relief in mouse models of chronic pain.

Local injections of botulinum toxins have been reported to be useful not only for the treatment peripheral neuropathic pain and migraine but also cause long-lasting muscle paralysis, a potentially serious side effect. Recently, A-based molecule ("BiTox") has synthesized that retains neuronal silencing capacity without triggering paralysis. In this study, we examined whether BiTox delivered peripherally was able reduce or prevent increased nociceptive sensitivity found in animal models...

Chronic pain affects one in five people across human societies, with few therapeutic options available. Botulinum neurotoxin (BoNT) can provide long-lasting relief by inhibiting local release of neuropeptides and neurotransmitters, but its highly paralytic nature has limited analgesic potential. Recent advances protein engineering have raised the possibility synthesising non-paralysing botulinum molecules for translation to sufferers. However, synthesis these molecules, via several synthetic...

Abstract Histone deacetylases ( HDAC s), 2 in particular, have been shown to regulate various forms of learning and memory. Since cognitive processes share mechanisms with spinal nociceptive signalling, we decided investigate the expression dorsal horn after peripheral injury. Using immunohistochemistry, found that was mainly seen neurons astrocytes, neuronal naïve tissue 2.6 times greater than astrocytes. Cysteine (S)‐nitrosylation releases gene silencing is controlled by nitric oxide NO )....

Abstract Background Epigenetic changes can bring insight into gene regulatory mechanisms associated with disease pathogenicity, including chronicity and increased vulnerability. To date, we are yet to identify genes sensitive epigenetic regulation that contribute the maintenance of chronic pain an landscape indicative susceptibility persistent pain. Such would provide a novel opportunity for better management, as their profile could be targeted treatment or used indication vulnerability...

Abstract Phosphorylation of histone H3 at serine 10 (p-H3S10) is a marker active gene transcription. Using cognitive models neural plasticity, p-H3S10 was shown to be downstream extracellular signal-regulated kinase (ERK) signalling in the hippocampus. In this study, we show that nociceptive after peripheral formalin injection increased expression ipsilateral dorsal horn. This increase maximal 30 minutes and occurred mainly within p-ERK-positive neurons. Spinal p-H3S10-enhanced also observed...

The rostral anterior cingulate cortex (rACC) has been implicated in the negative affective response to injury, and importantly, it shown that activation of extracellular signal-regulated kinase (ERK) signaling rACC contributes full expression component pain rodents. In this study, we investigated whether administration anesthesia at time injury could reduce phosphorylated-ERK (PERK) rACC, which might eliminate noxious stimulation. Intraplantar hindpaw formalin stimulation, an aversive event...

<title>Abstract</title> Chronic pain states are challenging to control with current drug therapies. Here, we demonstrate that a single dose of psilocybin can produce sustained anti-nociceptive effect in mouse model chronic neuropathic pain. Beyond this, the caused dramatic increase potential gabapentin, widely used treatment for pain, such data suggestive establishment longer lasting changes network processing.

Abstract There is an urgent need for new pain-relieving therapies. We have previously shown using mouse models of persistent pain that a single intrathecal injection substance P conjugated to the light chain botulinum toxin (SP-BOT) silenced neurons in dorsal horn spinal cord and alleviated mechanical hypersensitivity. The SP-BOT construct selectively neurokinin 1 receptor positive (NK1R+) superficial cord. A subset these NK1R+ are nociceptive projection convey injury-related information...