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1.  Analgesia for neuropathic pain by dorsal root ganglion transplantation of genetically engineered mesenchymal stem cells: initial results 
Molecular Pain  2015;11:5.
Cell-based therapy may hold promise for treatment of chronic pain. Mesenchymal stem cells (MSCs) are readily available and robust, and their secretion of therapeutic peptides can be enhanced by genetically engineering. We explored the analgesic potential of transplanting bone marrow-derived MSCs that have been transduced with lentivectors. To optimize efficacy and safety, primary sensory neurons were targeted by MSC injection into the dorsal root ganglia (DRGs).
MSCs were transduced using lentivectors to express enhanced green fluorescent protein (EGFP) or to co-express the analgesic peptide glial cell line-derived neurotrophic factor (GDNF) and EGFP by a viral 2A bicistronic transgene cassette. Engineered MSCs were injected into the 4th lumbar (L4) and L5 DRGs of adult allogeneic rats to evaluate survival in the DRGs. MSCs were detected by immunofluorescence staining up to 2–3 weeks after injection, distributed in the extracellular matrix space without disrupting satellite glial cell apposition to sensory neurons, suggesting well-tolerated integration of engrafted MSCs into DRG tissue. To examine their potential for inhibiting development of neuropathic pain, MSCs were injected into the L4 and L5 DRGs ipsilateral to a spinal nerve ligation injury. Animals injected with GDNF-engineered MSCs showed moderate but significant reduction in mechanical allodynia and hyperalgesia compared to controls implanted with MSCs expressing EGFP alone. We also observed diminished long-term survival of allografted MSCs at 3 weeks, and the development of a highly-proliferating population of MSCs in 12% of DRGs after transplantation.
These data indicate that genetically modified MSCs secreting analgesic peptides could potentially be developed as a novel DRG-targeted cell therapy for treating neuropathic pain. However, further work is needed to address the challenges of MSC survival and excess proliferation, possibly with trials of autologous MSCs, evaluation of clonally selected populations of MSCs, and investigation of regulation of MSC proliferation.
PMCID: PMC4331376
Mesenchymal stem cells; Glial cell line-derived neurotrophic factor; Neuropathic pain; Dorsal root ganglion; Lentivector
2.  Types of skin afferent fibers and spinal opioid receptors that contribute to touch-induced inhibition of heart rate changes evoked by noxious cutaneous heat stimulation 
Molecular Pain  2015;11:4.
In anesthetized rats and conscious humans, a gentle touch using a soft disc covered with microcones (with a texture similar to that of a finger), but not with a flat disc, inhibits nociceptive somatocardiac reflexes. Such an inhibitory effect is most reliably evoked when touch is applied to the skin ipsilateral and closest to nociceptive inputs. However, the mechanism of this inhibition is not completely elucidated. We aimed to clarify the types of cutaneous afferent fibers and spinal opioid receptors that contribute to antinociceptive effects of microcone touch.
The present study comprised two experiments with urethane-anesthetized rats. In the first experiment, unitary activity of skin afferent fibers was recorded from the saphenous nerve, and responses to a 10-min touch using a microcone disc and a flat disc (control) were compared. Greater discharge rate during microcone touch was observed in low-threshold mechanoreceptive Aδ and C afferent units, whereas many Aβ afferents responded similarly to the two types of touch. In the second experiment, the effect of an intrathecal injection of opioid receptor antagonists on the inhibitory effects of microcone touch on heart rate responses to noxious heat stimulation was examined. The magnitude of the heart rate response was significantly reduced by microcone touch in rats that received saline or naltrindole (δ-opioid receptor antagonist) injections. However, such an inhibition was not observed in rats that received naloxone (non-selective opioid receptor antagonist) or Phe-Cys-Tyr-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; μ-opioid receptor antagonist) injections.
Microcone touch induced greater responses of low-threshold mechanoreceptive Aδ and C afferent units than control touch. The antinociceptive effect of microcone touch was abolished by intrathecal injection of μ-opioid receptor antagonist. These results suggest that excitation of low-threshold mechanoreceptive Aδ and C afferents produces the release of endogenous μ-opioid ligands in the spinal cord, resulting in the inhibition of nociceptive transmission that contributes to somatocardiac reflexes.
PMCID: PMC4335417
Touch; Skin; Low-threshold mechanoreceptors; Noxious stimulation; Cardiovascular system; Spinal cord; μ-opioid receptor
3.  Protein kinase Cδ mediates histamine-evoked itch and responses in pruriceptors 
Molecular Pain  2015;11:1.
Itch-producing compounds stimulate receptors expressed on small diameter fibers that innervate the skin. Many of the currently known pruritogen receptors are Gq Protein-Coupled Receptors (GqPCR), which activate Protein Kinase C (PKC). Specific isoforms of PKC have been previously shown to perform selective functions; however, the roles of PKC isoforms in regulating itch remain unclear. In this study, we investigated the novel PKC isoform PKCδ as an intracellular modulator of itch signaling in response to histamine and the non-histaminergic pruritogens chloroquine and β-alanine.
Behavioral experiments indicate that PKCδ knock-out (KO) mice have a 40% reduction in histamine-induced scratching when compared to their wild type littermates. On the other hand, there were no differences between the two groups in scratching induced by the MRGPR agonists chloroquine or β-alanine. PKCδ was present in small diameter dorsal root ganglion (DRG) neurons. Of PKCδ-expressing neurons, 55% also stained for the non-peptidergic marker IB4, while a smaller percentage (15%) expressed the peptidergic marker CGRP. Twenty-nine percent of PKCδ-expressing neurons also expressed TRPV1. Calcium imaging studies of acutely dissociated DRG neurons from PKCδ-KO mice show a 40% reduction in the total number of neurons responsive to histamine. In contrast, there was no difference in the number of capsaicin-responsive neurons between KO and WT animals. Acute pharmacological inhibition of PKCδ with an isoform-specific peptide inhibitor (δV1-1) also significantly reduced the number of histamine-responsive sensory neurons.
Our findings indicate that PKCδ plays a role in mediating histamine-induced itch, but may be dispensable for chloroquine- and β-alanine-induced itch.
PMCID: PMC4298070  PMID: 25558916
PKC isoform; PKCdelta; Novel PKC; Peptide inhibitor; Pruritus
4.  Genetic, epigenetic, and mechanistic studies of temporomandibular disorders and overlapping pain conditions 
Molecular Pain  2014;10(1):72.
Leaders in the fields of Temporomandibular Disorders (TMD) and its accompanying overlapping pain conditions presented their latest findings at the Seventh Scientific Meeting of The TMJ Association, September 7–9, 2014, in Bethesda, MD. The meeting was co-sponsored by The TMJ Association and the National Institutes of Health. Topics of the scientific sessions included epidemiology and diagnostic criteria, basic mechanisms of chronic pain including the genetic and epigenetic basis of chronic pain, and the development of novel drugs for treatment of these conditions. Discussions were directed toward formulating a set of recommendations to advance research in this field.
PMCID: PMC4269918  PMID: 25511046
5.  Translational research in the genomic era: OPPERA study 
Molecular Pain  2014;10(Suppl 1):O1.
PMCID: PMC4304348  PMID: 25521492
6.  A cellular mechanism of interactions between pain and depression 
Molecular Pain  2014;10(Suppl 1):O10.
PMCID: PMC4304350
7.  Molecular correlates of localized versus co-occurring chronic pain conditions 
Molecular Pain  2014;10(Suppl 1):O11.
PMCID: PMC4304352
10.  The neurobiology of oral cancer pain 
Molecular Pain  2014;10(Suppl 1):O14.
PMCID: PMC4304358
11.  Mechanisms of chronic pain 
Molecular Pain  2014;10(Suppl 1):O15.
PMCID: PMC4304360
15.  Imaging orofacial pain in mice 
Molecular Pain  2014;10(Suppl 1):O2.
PMCID: PMC4304368
17.  Integrating epigenetic data into molecular casual networks 
Molecular Pain  2014;10(Suppl 1):O21.
PMCID: PMC4304370
20.  Roles of COMT, NPY and GCH1 in acute and chronic pain/stress response 
Molecular Pain  2014;10(Suppl 1):O5.
PMCID: PMC4304376
23.  Modeling TMJD pain in the laboratory mouse: role of TRP ion channels 
Molecular Pain  2014;10(Suppl 1):O8.
PMCID: PMC4304387
24.  Pain in the network of genetic and epigenetic control 
Molecular Pain  2014;10(Suppl 1):O9.
PMCID: PMC4304389

Results 1-25 (722)