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Minocycline Relieves Depressive-Like Behaviors in Rats With Bone Cancer Pain by Inhibiting Microglia Activation in Hippocampus.

Pain and depression are highly prevalent symptoms in cancer patients. They tend to occur simultaneously and affect each other and share biological pathways and neurotransmitters. In this study, we investigated the roles of microglia in the hippocampus in the comorbidity of bone cancer pain and depressive-like behaviors in an animal model of bone cancer pain.

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Mouse parabrachial neurons signal a relationship between bitter taste and nociceptive stimuli.

Taste and somatosensation both mediate protective behaviors. Bitter taste guides avoidance of ingestion of toxins while pain sensations, such as noxious heat, signal adverse conditions to ward off harm. Although brain pathways for taste and somatosensation are typically studied independently, prior data suggest they intersect, potentially reflecting their common protective role. To investigate this, we applied electrophysiologic and optogenetic techniques in anesthetized mice of both sexes to evaluate relationships between oral somatosensory and taste activity in the parabrachial nucleus (PbN), implicated for roles in gustation and pain. Spikes were recorded from taste-active PbN neurons tested with oral delivery of thermal and chemesthetic stimuli, including agonists of nocisensitive transient receptor potential (TRP) ion channels on somatosensory fibers. Gustatory neurons were also tested to follow electrical pulse stimulation of an oral somatosensory region of the spinal trigeminal subnucleus caudalis (Vc), which projects to the PbN. Neurons composed classic taste groups, including sodium, electrolyte, appetitive, or bitter cells. Across groups, most neurons spiked to Vc pulse stimulation, implying trigeminal projections reach PbN gustatory neurons. Among such cells, a subpopulation responsive to the bitter taste stimuli quinine and cycloheximide, and aversive concentrations of sodium, co-fired to agonists of nocisensitive TRP channels, including capsaicin, mustard oil, and noxious heat. Such neurons populated the lateral PbN. Further, nociceptive activity in PbN bitter taste neurons was suppressed during optogenetic-assisted inhibition of the Vc, implying convergent trigeminal input contributed to such activity. Our results reveal a novel role for PbN gustatory cells in cross-system signaling related to protection.Prior data suggest gustatory and trigeminal neural pathways intersect and overlap in the parabrachial area. However, no study has directly examined such overlap and why it may exist. Here we found that parabrachial gustatory neurons can receive afferent projections from trigeminal nuclei and fire to oral nociceptive stimuli that excite somatosensory receptors and fibers. Activation to aversive nociceptive stimuli in gustatory cells was associated with responding to behaviorally-avoided bitter tastants. We were further able to show that silencing trigeminal projections inhibited nociceptive activity in parabrachial bitter taste neurons. Our results imply that in the parabrachial area, there is predictable overlap between taste and somatosensory processing related to protective coding and that classically-defined taste neurons contribute to this process.

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Cold sensing by Na1.8-positive and Na1.8-negative sensory neurons.

The ability to detect environmental cold serves as an important survival tool. The sodium channels Na1.8 and Na1.9, as well as the TRP channel Trpm8, have been shown to contribute to cold sensation in mice. Surprisingly, transcriptional profiling shows that Na1.8/Na1.9 and Trpm8 are expressed in nonoverlapping neuronal populations. Here we have used in vivo GCaMP3 imaging to identify cold-sensing populations of sensory neurons in live mice. We find that ∼80% of neurons responsive to cold down to 1 °C do not express Na1.8, and that the genetic deletion of Na1.8 does not affect the relative number, distribution, or maximal response of cold-sensitive neurons. Furthermore, the deletion of Na1.8 had no observable effect on transient cold-induced (≥5 °C) behaviors in mice, as measured by the cold-plantar, cold-plate (5 and 10 °C), or acetone tests. In contrast, nocifensive-like behavior to extreme cold-plate stimulation (-5 °C) was completely absent in mice lacking Na1.8. Fluorescence-activated cell sorting (FACS) and subsequent microarray analysis of sensory neurons activated at 4 °C identified an enriched repertoire of ion channels, which include the Trp channel Trpm8 and potassium channel Kcnk9, that are potentially required for cold sensing above freezing temperatures in mouse DRG neurons. These data demonstrate the complexity of cold-sensing mechanisms in mouse sensory neurons, revealing a principal role for Na1.8-negative neurons in sensing both innocuous and acute noxious cooling down to 1 °C, while Na1.8-positive neurons are likely responsible for the transduction of prolonged extreme cold temperatures, where tissue damage causes pan-nociceptor activation.

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Single cell q-PCR derived expression profiles of identified sensory neurons.

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Silencing of spinal Trpv1 attenuates neuropathic pain in rats by inhibiting CAMKII expression and ERK2 phosphorylation.

Accumulating evidence suggests a potential role of transient receptor potential vanilloid 1 (TRPV1) channels in inflammatory and cancer-related pain. However, the role of TRPV1 in the maintenance of neuropathic pain remains elusive. The current study investigated the effects of transient Trpv1 gene silencing using a small interference RNA (siRNA) on neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve in rats. Seven days after CCI, the TRPV1 siRNA was intrathecally administered (5 µg/15 µl, once daily for 2 days). TRPV1 and Ca/calmodulin-dependent protein kinase II (CAMKII) expression and extracellular signal-regulated kinase (ERK) phosphorylation in the spinal cord were detected using western blotting. The thresholds to mechanical and thermal stimuli were determined before and after intrathecal TRPV1 siRNA administration. TRPV1 and CAMKII expression and ERK2 phosphorylation in the spinal cord were upregulated after CCI. Intrathecal administration of the TRPV1 siRNA not only attenuated behavioural hyperalgesia but also reduced the expression of TRPV1 and CAMKII, as well as ERK2 phosphorylation. Based on these results, silencing of the TRPV1 gene in the spinal cord attenuates the maintenance of neuropathic pain by inhibiting CAMKII/ERK2 activation and suggests that TRPV1 represents a potential target in pain therapy.

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Downregulation of M-channels in lateral habenula mediates hyperalgesia during alcohol withdrawal in rats.

Hyperalgesia often occurs in alcoholics, especially during abstinence, yet the underlying mechanisms remain elusive. The lateral habenula (LHb) has been implicated in the pathophysiology of pain and alcohol use disorders. Suppression of m-type potassium channels (M-channels) has been found to contribute to the hyperactivity of LHb neurons of rats withdrawn from chronic alcohol administration. Here, we provided evidence that LHb M-channels may contribute to hyperalgesia. Compared to alcohol naïve counterparts, in male Long-Evans rats at 24-hours withdrawal from alcohol administration under the intermittent access paradigm for eight weeks, hyperalgesia was evident (as measured by paw withdrawal latencies in the Hargreaves Test), which was accompanied with higher basal activities of LHb neurons in brain slices, and lower M-channel protein expression. Inhibition of LHb neurons by chemogenetics, or pharmacological activation of M-channels, as well as overexpression of M-channels' subunit KCNQ3, relieved hyperalgesia and decreased relapse-like alcohol consumption. In contrast, chemogenetic activation of LHb neurons induced hyperalgesia in alcohol-naive rats. These data reveal a central role for the LHb in hyperalgesia during alcohol withdrawal, which may be due in part to the suppression of M-channels and, thus, highlights M-channels in the LHb as a potential therapeutic target for hyperalgesia in alcoholics.

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TIMP-1 attenuates the development of cutaneous inflammation-induced hypersensitivity.

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Combining naproxen and a dual amylin and calcitonin receptor agonist improves pain and structural outcomes in the collagen-induced arthritis rat model.

Pain is a debilitating symptom of rheumatoid arthritis (RA), caused by joint inflammation and cartilage and bone destruction. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat pain and inflammation in RA, but are not disease-modifying and do not prevent joint destruction when administered alone. KBPs (Key Bioscience peptides) are synthetic peptides based on salmon calcitonin and are expected to inhibit bone resorption and to be chondroprotective. In this study, we investigated if combining a standard of care NSAID (naproxen) with a KBP resulted in improvement in pain scores, as well as disease activity and structural damage in a rat model of RA.

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Sensory neuron-derived Nav1.7 contributes to dorsal horn neuron excitability.

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Orally consumed cannabinoids provide long-lasting relief of allodynia in a mouse model of chronic neuropathic pain.

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