European journal of pharmacology
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Glia plays a crucial role in the maintenance of neuronal homeostasis in the central nervous system. The microglial production of immune factors is believed to play an important role in nociceptive transmission. Pain may now be considered a neuro-immune disorder, since it is known that the activation of immune and immune-like glial cells in the dorsal root ganglia and spinal cord results in the release of both pro- and anti-inflammatory cytokines, as well as algesic and analgesic mediators. ⋯ The other way of pain control can be the decrease of pro-nociceptive agents like transcription factor synthesis (NF-kappaB, AP-1); kinase synthesis (MEK, p38MAPK, JNK) and protease activation (cathepsin S, MMP9, MMP2). Additionally, since it is known that the opioid-induced glial activation opposes opioid analgesia, some glial inhibitors, which are safe and clinically well tolerated, are proposed as potential useful ko-analgesic agents for opioid treatment of neuropathic pain. This review pointed to some important mechanisms underlying the development of neuropathic pain, which led to identify some possible new approaches to the treatment of neuropathic pain, based on the more comprehensive knowledge of the interaction between the nervous system and glial and immune cells.
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Multiple groups have reported the functional cross-regulation between mu-opioid (MOP) receptor and glutamate ionotropic receptor N (GluN), and the post-synaptic association of these receptors has been implicated in the transmission and modulation of nociceptive signals. Opioids, such as morphine, disrupt the MOP receptor-GluN receptor complex to stimulate the activity of GluN receptors via protein kinase C (PKC)/Src. This increased GluN receptor activity opposes MOP receptor signalling, and via neural nitric oxide synthase (nNOS) and calcium and calmodulin regulated kinase II (CaMKII) induces the phosphorylation and uncoupling of the opioid receptor, which results in the development of morphine analgesic tolerance. ⋯ Treatments that rescue morphine from analgesic tolerance, such as GluN receptor antagonism or PKC, nNOS and CaMKII inhibitors, all induce MOP receptor-GluN receptor re-association and reduce GluN receptor/CaMKII activity. In mice treated with NMDA or suffering from neuropathic pain (induced by chronic constriction injury, CCI), GluN receptor antagonists, PKA inhibitors or certain antidepressants also diminish CaMKII activity and restore the MOP receptor-GluN receptor association. Thus, the HINT1 protein stabilises the association between MOP receptor and GluN receptor, necessary for the analgesic efficacy of morphine, and this coupling is reduced following the activation of GluN receptors, similar to what is observed in neuropathic pain.
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The exploitation of preparations of Cannabis sativa to combat pain seems to date back to time immemorial, although their psychotropic effects, which are at the bases of their recreational use and limit their therapeutic use, are at least as ancient. Indeed, it has always been different to tease apart the unwanted central effects from the therapeutic benefits of Δ⁹-tetrahydrocannabinol (THC), the main psychotropic component of cannabis. ⋯ The advantages of this approach over direct activation of cannabinoid receptors as a therapeutic strategy against neuropathic and inflammatory pain are discussed here along with its potential complications. These latter have been such that clinical success has been achieved so far more rapidly with naturally occurring THC or endocannabinoid structural analogues acting at a plethora of cannabinoid-related and -unrelated molecular targets, than with selective inhibitors of endocannabinoid enzymatic hydrolysis, thus leading to revisit the potential usefulness of "multi-target" versus "magic bullet" compounds as new analgesics.
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Opioids are the oldest and most potent drugs for the treatment of severe pain. Their clinical application is undisputed in acute pain (e.g. associated with trauma or surgery) but their long-term use in chronic pain has met increasing scrutiny. ⋯ Since pain is a complex bio-psycho-social phenomenon, non-pharmacological considerations important for the understanding of opioid analgesic efficacy are also included. Finally, examples of challenging clinical situations such as the perioperative management of patients receiving long-term opioid treatment are illustrated.
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Significant social and financial burden due to wounds need newer drugs/formulations to speed up the healing process. Substance P (SP), a neuropeptide, is associated with release of various cytokines and growth factors from inflammatory, epithelial and endothelial cells. In the present study, temporal effects of topically applied SP (10(-7)M in normal saline) were evaluated in the modulation of various cytokines and growth factors that participate in cutaneous wound healing. ⋯ Histopathological evaluation of hematoxylin and eosin stained wound sections showed that SP treatment produced increased early leukocytes infiltration, fibroblast proliferation, angiogenesis, collagen deposition and re-epithelialization. Results of the present study demonstrate that topical application of SP enhanced wound healing by modulating cytokines, growth factors and cells. Based on the results, it is suggested that SP could be of beneficial use in diabetic wounds where levels of VEGF, TGF-β1 and SP decrease along with impairment of inflammatory reaction.