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The aim of this study was to examine the inhibitory effect of teriparatide (TPTD) on pain and on bone loss in ovariectomized (OVX) mice. The mechanism of osteoporotic pain in OVX mice was evaluated through an examination of pain-related behavior as well as immunohistochemical examinations.
Learn More >We have examined the regulation of mutually exclusive Cav2.2 exon 37a and b variants by the mouse μ-opioid receptor (mMOR) C-terminal splice variants 1, 1C and 1O in tsA-201 cells. Electrophysiological analyses revealed that both channel isoforms exhibit DAMGO-induced voltage-dependent (Gβγ-mediated) inhibition and its recovery by voltage pre-pulses, as well as a voltage-independent component. However, the two channel isoforms differ in their relative extent of voltage-dependent and independent inhibition, with Cav2.2-37b showing significantly more voltage-dependent inhibition upon activation of the three mMOR receptors studied. In addition, coexpression of either mMOR1 or mMOR1C results in an agonist-independent reduction in the peak current density of Cav2.2-37a channels, whereas the peak current density of Cav2.2-37b does not appear to be affected. Interestingly, this decrease is not due to an effect on channel expression at the plasma membrane, as demonstrated by biotinylation experiments. We further examined the mechanism underlying the agonist-independent modulation of Cav2.2-37a by mMOR1C. Incubation of cells with pertussis toxin did not affect the mMOR1C mediated inhibition of Cav2.2-37a currents, indicating a lack of involvement of Gi/o signaling. However, when a Src tyrosine kinase inhibitor was applied, the effect of mMOR1C was lost. Moreover, when we recorded currents using a Cav2.2-37a mutant in which tyrosine 1747 was replaced with phenylalanine (Y1747F), the agonist independent effects of mMOR1C were abolished. Altogether our findings show that Cav2.2-37a and Cav2.2-37b isoforms are subject to differential regulation by C-terminal splice variants of mMORs, and that constitutive mMOR1C activity and downstream tyrosine kinase activity exert a selective inhibition of the Cav2.2-37a splice variant, an N-type channel isoform that is highly enriched in nociceptors. Our study provides new insights into the roles of the MOR full-length C-terminal variants in modulating Cav2.2 channel isoform activities.
Learn More >This article reviews the role of analgesic drugs with a particular emphasis on opioids. Opioids are the oldest and most potent drugs for the treatment of severe pain, but they are burdened by detrimental side effects such as respiratory depression, addiction, sedation, nausea, and constipation. Their clinical application is undisputed in acute (e.g., perioperative) and cancer pain, but their long-term use in chronic pain has met increasing scrutiny and has contributed to the current opioid crisis. We discuss epidemiological data, pharmacological principles, clinical applications, and research strategies aiming at novel opioids with reduced side effects.
Learn More >The treatment of chronic pain is poorly managed by current analgesics, and there is a need for new classes of drugs. We recently developed a series of bioactive lipids that inhibit the human glycine transporter GlyT2 (SLC6A5) and provide analgesia in animal models of pain. Here, we have used functional analysis of mutant transporters combined with molecular dynamics simulations of lipid-transporter interactions to understand how these bioactive lipids interact with GlyT2. This study identifies a novel extracellular allosteric modulator site formed by a crevice between transmembrane domains 5, 7, and 8, and extracellular loop 4 of GlyT2. Knowledge of this site could be exploited further in the development of drugs to treat pain, and to identify other allosteric modulators of the SLC6 family of transporters.
Learn More >Sleep quality and chronic neck pain (NP) are associated. However, the genetic influences on this association have not been explored. This study investigated the genetic and environmental influences on the association between sleep quality and chronic NP.
Learn More >Contributors to the ongoing epidemic of prescription opioid abuse, addiction, and death include opioid tolerance, withdrawal symptoms, and possibly opioid-induced hyperalgesia (OIH). Thirty stable chronic non-malignant pain patients entered a six-month long, randomized, double-blind, dose-response, two-center trial of the potent opioid levorphanol, conducted over a decade ago during an era of permissive opioid prescribing. Eleven were taking no opioids at study entry and eleven were taking between 35-122 morphine equivalents (MEQ). Five weeks titration preceded twenty weeks stable dosing. Tolerance and OIH were inferred individually based on chronic pain ratings, Brief Pain Inventory scores, and results of the Brief Thermal Sensitization (BTS) model at five opioid dosing sessions. Seventeen patients completed. The average final daily opioid dose was 132; range 14-300; average addition 105 MEQ. After observed dosing, the BTS area of hyperalgesia changed minimally but the painfulness of skin heating was reduced. Weekly 0-100 VAS pain ratings (average 64 at study entry, 48 at end titration, 45 at end stable dosing) decreased a median 19%, but eight completed with higher VAS ratings. Three completers had evidence of both tolerance and hyperalgesia. A fully-powered trial similar to this feasibility study is ethically questionable. A large-scale pragmatic trial is more realistic. Trial Registration: NCT00275249 Evolution of Analgesic Tolerance With Opioids Perspective: A double-blind, six-month, high-dose opioid feasibility trial, completed years ago, provides critically important data for clinically defining analgesic tolerance and opioid-induced hyperalgesia (OIH). Overall benefit was small, and 18% of patients had evidence of both tolerance and OIH. Future work requires a different approach than a classic RCT design.
Learn More >Past studies have shown that pain memories are often inaccurate, a phenomenon known as mnemonic pain bias. Pain memories are thought to play an important role on how future pain is felt. Recent evidence from our laboratory suggests that individuals who exaggerate past pain display increased superior temporal gyrus (STG) and parahippocampal gyrus (PHG) activity during the encoding of experimental painful stimulations, suggesting that these brain structures play an important role in pain memories.
Learn More >To investigate whether intravenously infused provokes migraine aura and migraine headache in migraine patients with aura.
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