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Cochrane is an international non-profit organization established in 1993 to produce and disseminate high quality and unbiased systematic reviews of evidence on health care interventions. At the forefront of systematic review methodology, Cochrane is generally accepted to be among the most carefully prepared and rigorous sources of systematic review evidence. There are numerous Cochrane reviews on nonpharmacologic interventions for pain and multiple Cochrane reviews evaluating acupuncture therapy in pain conditions. But how complete and up to date are those reviews relative to other rigorous systematic reviews with meta-analyses of acupuncture therapy for pain published in the literature? In this 'snapshot' overview, we found 22 relevant Cochrane reviews, some concluding that acupuncture therapy is probably useful for treating specific pain conditions. However, many of the conditions for which acupuncture is most commonly used are either not represented in Cochrane reviews or the existing Cochrane reviews are seriously outdated and do not reflect current evidence. This creates confusion with the risks of adverse effects and addiction liability associated with pain medications, the prevalence of chronic pain, the ongoing opioid epidemic and the need for evidence-based options for pain as part of comprehensive pain care. Clinicians and patients want clarification on safe and effective options to treat pain. Issues involving reviewed trials' inadequate use of sham comparators, of acupuncture as a complex intervention with interactive components and a shift in research focus from efficacy trials to real-world pragmatic trials are discussed in relation to updating Cochrane reviews of acupuncture therapy for pain.
Learn More >Pain is more prevalent in women for reasons that remain unclear. We have identified a mechanism of injury-free nociceptor sensitization and opioid-induced hyperalgesia (OIH) promoted by prolactin (PRL) in females. PRL signals through mutually inhibitory long (PRLR-L) and short (PRLR-S) receptor isoforms, and PRLR-S activation induces neuronal excitability. PRL and PRLR expression were higher in females. CRISPR-mediated editing of PRLR-L promoted nociceptor sensitization and allodynia in naïve, uninjured female mice that depended on circulating PRL. Opioids, but not trauma-induced nerve injury, decreased PRLR-L promoting OIH through activation of PRLR-S in female mice. Deletion of both PRLR-L and PRLR-S (total PRLR) prevented, whereas PRLR-L overexpression rescued established OIH selectively in females. Inhibition of circulating PRL with cabergoline, a dopamine D2 agonist, up-regulated PRLR-L and prevented OIH only in females. The PRLR-L isoform therefore confers protection against PRL-promoted pain in females. Limiting PRL/PRLR-S signaling pharmacologically or with gene therapies targeting the PRLR may be effective for reducing pain in a female-selective manner.
Learn More >While much brain research on fibromyalgia (FM) focuses on the study of hyper-responsiveness to painful stimuli, some studies suggest that the increased pain-related brain activity often reported in FM studies may be in part explained by stronger responses to salient aspects of the stimulation rather than, or in addition to, its painfulness. We thus hypothesized that FM patients would demonstrate elevated brain responses to both pain onset and offset, two salient sensory events of opposing valences.
Learn More >Intra-epidermal nerve endings progress within keratinocyte cytoplasmic tunnels in normal human skin.
Intra-epidermal nerve endings, responsible for cutaneous perception of temperature, pain and itch, are conventionally described as passing freely between keratinocytes, from the basal to the granular layers of the epidermis. However, the recent discovery of keratinocyte contribution to cutaneous nociception implies that their anatomical relationships are much more intimate than what has been described so far. By studying human skin biopsies in confocal laser-scanning microscopy, we show that intra-epidermal nerve endings are not only closely apposed to keratinocytes, but can also be enwrapped by keratinocyte cytoplasms over their entire circumference and thus progress within keratinocyte tunnels. As keratinocytes must activate intra-epidermal nerve endings to transduce nociceptive information, these findings may help understanding the interactions between the keratinocytes and nervous system. The discovery of these nerve portions progressing in keratinocyte tunnels is a strong argument to consider that contacts between epidermal keratinocytes and intra-epidermal nerve endings are not incidental and argues for the existence of specific and rapid paracrine communication from keratinocytes to sensory neurons.
Learn More >To examine the distribution and patterns of opioid prescribing in the United States.
Learn More >Opioid-sparing adjuncts are treatments that aim to reduce the overall dose of opioids needed to achieve analgesia, hence decreasing the burden of side effects through alternative mechanisms of action. Lorcaserin is a serotonin 5-HT receptor (5-HTR) agonist that has recently been reported to reduce abuse-related effects of the opioid analgesic oxycodone. The goal of our studies was to evaluate the effects of adjunctive lorcaserin on opioid-induced analgesic-like behavior using the tail-flick reflex (TFR) test as a mouse model of acute thermal nociception. We show that whereas subcutaneous (s.c.) administration of lorcaserin alone was inactive on the TFR test, adjunctive lorcaserin (s.c.) significantly increased the potency of oxycodone as an antinociceptive drug. This effect was prevented by the 5-HTR antagonist SB242084. A similar lorcaserin (s.c.)-induced adjunctive phenotype was observed upon administration of the opioid analgesics morphine and fentanyl. Remarkably, we also show that, opposite to the effects observed via s.c. administration, intrathecal (i.t.) administration of lorcaserin alone induced antinociceptive TFR behavior, an effect that was not prevented by the opioid receptor antagonist naloxone. This route of administration (i.t.) also led to a significant augmentation of oxycodone-induced antinociception. Lorcaserin (s.c.) did not alter the brain or blood concentrations of oxycodone, which suggests that its adjunctive effects on opioid-induced antinociception do not depend upon changes in opioid metabolism. Together, these data indicate that lorcaserin-mediated activation of the 5-HTR may represent a new pharmacological approach to augment opioid-induced antinociception.
Learn More >Following destabilization of the medial meniscus (DMM), mice develop experimental osteoarthritis (OA) and associated pain behaviors that are dependent on the stage of disease. We aimed to describe changes in gene expression in knee-innervating dorsal root ganglia (DRG) after surgery, in order to identify molecular pathways associated with three pre-defined pain phenotypes: "post-surgical pain", "early-stage OA pain", and "persistent OA pain".
Learn More >Migraine headache pathophysiology involves trigeminovascular system activation, calcitonin gene-related peptide (CGRP) release and dysfunctional nociceptive transmission. Triptans are 5-HT1B/1D/(1F) receptor agonists that prejunctionally inhibit trigeminal CGRP release, but their vasoconstrictor properties limit their use in migraine patients with cardiovascular disease. In contrast, lasmiditan is a novel antimigraine and selective 5-HT1F receptor agonist devoid of vasoconstrictor properties. On this basis, the present study has investigated the modulation of trigeminal CGRP release by lasmiditan.For this purpose, we have comparatively analysed the inhibition of several components of the trigeminovascular system induced by lasmiditan and sumatriptan through: ex vivo KCl-induced CGRP release from isolated dura mater, trigeminal ganglion and trigeminal nucleus caudalis of mice; and in vivo dural vasodilation in the rat closed-cranial window model induced by endogenous (electrical stimulation, capsaicin) and exogenous CGRP.The ex vivo release of CGRP was similarly inhibited by sumatriptan and lasmiditan in all trigeminovascular system components. In vivo, i.v. lasmiditan or higher doses of sumatriptan significantly attenuated the vasodilatory responses to endogenous CGRP release, but not exogenous CGRP effects. These data suggest that lasmiditan prejunctionally inhibits CGRP release in peripheral and central trigeminal nerve terminals. Since lasmiditan is a lipophilic drug that crosses the blood-brain barrier, additional central sites of action remain to be determined.
Learn More >Neuropathic pain causes severe suffering, and most patients are resistant to current therapies. A core element of neuropathic pain is the loss of inhibitory tone in the spinal cord. Previous studies have shown that foetal GABAergic neuron precursors can provide relief from pain. However, the source of these precursor cells and their multipotent status make them unsuitable for therapeutic use. Here, we extend these findings by showing, for the first time, that spinally transplanted, terminally differentiated human induced pluripotent stem cell-derived GABAergic (iGABAergic) neurons provide significant, long-term, and safe relief from neuropathic pain induced by peripheral nerve injury in mice. Furthermore, iGABAergic neuron transplants survive long term in the injured spinal cord and show evidence of synaptic integration. Together, this provides the proof in principle for the first viable GABAergic transplants to treat human neuropathic pain patients.
Learn More >The hypothalamus plays a key role in both migraine and cluster headache (CH). As brain region-to-region structural correlations are believed to reflect structural and functional brain connectivity patterns, we assessed the structural covariance patterns between the volume of the hypothalamic region and vertex-by-vertex measurements of cortical thickness in patients with migraine and in those with CH relative to healthy controls (HC).
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