European journal of pain : EJP
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The transient receptor potential vanilloid receptor 1 (TRPV1) is a nonselective cation channel involved in the mediation of peripheral pain to the central nervous system. As such, the TRPV1 is an accessible molecular target that lends itself well to the understanding of nociceptive signalling. This study encompasses preclinical investigations of three molecules with the prospect to establish them as suitable analgesic model compounds in human intradermal pain relief studies. ⋯ This work details the pharmaceutical work-up of three TRPV1-active investigational compounds, to obtain regulatory approval, for subsequent use in humans. This fast and cost-effective preclinical development path may impact research beyond the pain management area, as it allows human target engagement information gathering early in drug development.
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The mechanisms underlying sex-based differences in pain and analgesia are poorly understood. In this study, we investigated gene expression changes in trigeminal ganglia (TG) of male and female rats exposed to infraorbital nerve chronic constriction injury (IoN-CCI). ⋯ We present novel sex-specific transcriptional regulation in trigeminal ganglia that may contribute to male-/female-based differences in trigeminal neuropathic pain. These findings are expected to open new research horizons, particularly in male versus female targeted therapeutic regimens.
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Prostaglandin E2 (PGE2) enriched in inflamed tissues contributes to chronic pain by sensitizing nociceptive dorsal root ganglion (DRG) neurons (nociceptors). Of four PGE2 receptors (EP1-4), EP4 plays a major role in PGE2-induced nociceptor sensitization. We have previously reported that PGE2 or EP4 agonists stimulated EP4 externalization in cultured DRG neurons and this event contributes to nociceptor sensitization. However, the signalling transduction events governing this event remain unknown. ⋯ This study adds mechanistic information regarding signalling transduction events involved in agonist-induced EP4 cell surface trafficking. EP4 and EP2 (to lesser extent) receptors, extra- and intracellular Ca++ , CaKMII, cAMP, PKA, PKC, PKCε, PLC, MAPK, PI3K and Akt are involved in this event. Agonist-induced EP4 externalization contributes to enhanced nociceptor sensitization.
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Randomized Controlled Trial
Predicting drug efficacy in chronic low back pain by quantitative sensory tests.
Drugs are prescribed for chronic low back pain without knowing in advance whether a patient will respond to them or not. Quantitative sensory tests (QST) can discriminate patients according to sensory phenotype, possibly reflecting underlying mechanisms of pain processing. QST may therefore be a screening tool to identify potential responders to a certain drug. The aim of this study was to investigate whether QST can predict analgesic effects of oxycodone, imipramine and clobazam in chronic low back pain. ⋯ Predicting drug efficacy in chronic low back pain remains difficult. There is some evidence that patients more sensitive to heat and cold pain respond better to imipramine.
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The objectives of the current study were to investigate (1) the longitudinal, reciprocal associations between pain and post-traumatic stress symptoms as proposed by the mutual maintenance model, and (2) to assess the predictive value of the three clusters of post-traumatic stress, where the model revealed that post-traumatic stress symptoms maintained pain in a consecutive cohort of whiplash-injured. ⋯ Investigating mutual maintenance of pain and PTSS in whiplash, the present study found evidence suggesting a maintaining effect of PTSS on pain within the first 3 months post-injury and from 6 to 12 months driven by hyperarousal, highlighting the importance of addressing PTSS.