Articles: hyperalgesia.
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Randomized Controlled Trial
GABAergic modulation of Secondary hyperalgesia: A randomized controlled 4-way crossover trial with the α2-subunit preferring GABA positive allosteric modulator, N-Desmethyl-Clobazam in healthy volunteers.
The antihyperalgesic and sedative effects of the α2-subunit preferring GABAA positive allosteric modulator (GAM), N-desmethyl-clobazam (NDMC), 20 and 60 mg, were assessed in a randomized, placebo and active-controlled (clonazepam 1,5 mg), 4-way crossover study, in healthy volunteers, using the ultraviolet B-induced experimental pain model. Single (20, 40, 60 mg) and repeated doses (20 mg over 15 days) of NDMC pharmacokinetics were evaluated. Thirty-two subjects participated in the study. ⋯ NDMC absence of sedative effect and its overall well-characterized safety coming from years of utilization as a metabolite from clobazam, raise the prospect of dose escalating trials in patients to quantify its clinical utility. SIGNIFICANCE: This article, presenting the Phase I data of the new antihyperalgesic compound, α2-subunit GABAA positive allosteric modulator, N-desmethyl-clobazam (NDMC) is exploring the modulation of a new target in the treatment of neuropathic pain. Based on these results and on its preclinical properties NDMC would qualify as a good tool compound to seek confirmation of the clinical utility of selective GABA allosteric modulators in neuropathic pain patients.
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Spontaneous pain after surgical incision is a significant problem for most post-operative patients. Pain management that relies on opioids is hindered by numerous side effects, fuelling interest in non-opioid alternatives and multimodal approaches. Subcutaneous capsaicin infiltration has shown potential for reducing post-operative pain, but there are unanswered questions about safety and possible side effects. In adult rats, we characterized the analgesic effects of pre-operative capsaicin infiltration into the skin prior to plantar incision and assessed wound healing and epidermal innervation. ⋯ Pre-operative capsaicin infiltration attenuated spontaneous pain-like behaviour and prevented the development of heat hyperalgesia following plantar skin incision. While capsaicin caused long-lasting and widespread loss of epidermal and dermal nerve fibres, there was no measurable impact on the rate of wound healing. Pre- or intra-operative infiltration of capsaicin into surgical sites could act as a safe prophylactic for post-operative pain and reduce the need for opioids during recovery.
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NrCAM, a neuronal cell adhesion molecule in the L1 family of the immunoglobulin superfamily, is subjected to extensively alternative splicing and involved in neural development and some disorders. The aim of this study was to explore the role of Nrcam mRNA alternative splicing in neuropathic pain. A next generation RNA sequencing analysis of dorsal root ganglions (DRGs) showed the differential expression of two splicing variants of Nrcam, Nrcam+10 and Nrcam-10, in the injured DRG after the fourth lumbar spinal nerve ligation (SNL) in mice. ⋯ Nrcam ASO also relieved SNL- or chronic compression of DRG (CCD)-induced the maintenance of pain hypersensitivities in male and female mice. PERSPECTIVE: We conclude that the relative levels of alternatively spliced Nrcam variants are critical for neuropathic pain genesis. Targeting Nrcam alternative splicing via the antisense oligonucleotides may be a new potential avenue in neuropathic pain management.
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Anesthesia and analgesia · Jul 2020
Differential Regulation of the Glucocorticoid Receptor in a Rat Model of Inflammatory Pain.
Anti-inflammatory corticosteroids are a common treatment for different conditions involving chronic pain and inflammation. Clinically used steroids target the glucocorticoid receptor (GR) for its anti-inflammatory effects. We previously reported that GR in sensory neurons may play central roles in some pain models and that GR immunoreactivity signal in dorsal root ganglia (DRG) decreased after local inflammation of the DRG (a model of low back pain). In the current study, we aimed to determine if similar changes in GR signal also exist in a skin inflammation model, the complete Freund's adjuvant (CFA) model (a model of peripheral inflammatory pain), in which the terminals of the sensory neurons rather than the somata are inflamed. ⋯ There are distinctive patterns of GR activation under different pain conditions, depending on the anatomical location. The observed downregulation of the GR in sensory neurons may have a significant impact on the use of steroids as treatment in these conditions and on the regulatory effects of endogenous glucocorticoids.
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Upon transient musculoskeletal diseases, some patients develop persistent pain while others recover from pain. Here, we studied whether such heterogeneity also occurs in rats after recovery from unilateral antigen-induced arthritis (AIA) in the knee joint, and which pain phenotype may predict the course of pain. Typically, inflammatory swelling lasts about 3 weeks. ⋯ However, none of the rats showed an expression of ATF3 in dorsal root ganglion neurons, nor morphological spinal microglia activation thus not suggesting development of neuropathic pain. Both clusters showed a persistent upregulation of pCREB in dorsal root ganglion neurons, inversely correlated with mechanical hyperalgesia at the knee. The role of pCREB needs to be further explored.