Optogenetic Manipulations of Amygdala Neurons Modulate Spinal Nociceptive Processing and Behavior Under Normal Conditions and in an Arthritis Pain Model.

The amygdala is an important neural substrate for the emotional-affective dimension of pain and modulation of pain. The central nucleus (CeA) serves major amygdala output functions and receives nociceptive and affected-related information from the spino-parabrachial and lateral-basolateral amygdala (LA-BLA) networks. The CeA is a major site of extra-hypothalamic expression of corticotropin releasing factor (CRF, also known as corticotropin releasing hormone, CRH), and amygdala CRF neurons form widespread projections to target regions involved in behavioral and descending pain modulation. Here we explored the effects of modulating amygdala neurons on nociceptive processing in the spinal cord and on pain-like behaviors, using optogenetic activation or silencing of BLA to CeA projections and CeA-CRF neurons under normal conditions and in an acute pain model. Extracellular single unit recordings were made from spinal dorsal horn wide dynamic range (WDR) neurons, which respond more strongly to noxious than innocuous mechanical stimuli, in normal and arthritic adult rats (5-6 h postinduction of a kaolin/carrageenan-monoarthritis in the left knee). For optogenetic activation or silencing of CRF neurons, a Cre-inducible viral vector (DIO-AAV) encoding channelrhodopsin 2 (ChR2) or enhanced Natronomonas pharaonis halorhodopsin (eNpHR3.0) was injected stereotaxically into the right CeA of transgenic Crh-Cre rats. For optogenetic activation or silencing of BLA axon terminals in the CeA, a viral vector (AAV) encoding ChR2 or eNpHR3.0 under the control of the CaMKII promoter was injected stereotaxically into the right BLA of Sprague-Dawley rats. For wireless optical stimulation of ChR2 or eNpHR3.0 expressing CeA-CRF neurons or BLA-CeA axon terminals, an LED optic fiber was stereotaxically implanted into the right CeA. Optical activation of CeA-CRF neurons or of BLA axon terminals in the CeA increased the evoked responses of spinal WDR neurons and induced pain-like behaviors (hypersensitivity and vocalizations) under normal condition. Conversely, optical silencing of CeA-CRF neurons or of BLA axon terminals in the CeA decreased the evoked responses of spinal WDR neurons and vocalizations, but not hypersensitivity, in the arthritis pain model. These findings suggest that the amygdala can drive the activity of spinal cord neurons and pain-like behaviors under normal conditions and in a pain model.

Transfer of the Serotonin Modulator Vortioxetine into Human Milk: A Case Series.

Background: Vortioxetine (Trintellix) is a serotonin modulator used in the treatment of major depressive disorder in adults. There are no data presently published on the transfer of vortioxetine into human breast milk. Case Report: The present study determined the drug concentration-time profile of vortioxetine in milk samples collected from three lactating mothers, two consuming 10 mg once daily and one consuming 20 mg once daily. Milk levels were measured using liquid chromatography mass spectrometry. At a dose of 10 mg/day, the maximum concentration of vortioxetine in milk was 13.89 ng/mL. At a dose of 20 mg/day, the maximum concentration in milk was 52.32 ng/mL. The relative infant dose was calculated to be 1.1% for 10 mg dose and 1.7% for 20 mg dose. Conclusion: In these three cases, we found the levels of vortioxetine in breast milk to be low and dose proportional. However, both RID's for 10 and 20 mg doses (1.1% and 1.7%, respectively) fall below the 10% theoretical level of concern and no adverse effects were reported by the mothers. As this is a small patient sample, caution should be exercised until further studies report the safety profile of vortioxetine in breastfeeding infants.

Rivaroxaban Treatment in Two Breastfeeding Mothers: A Case Series.

Background: Rivaroxaban (Xarelto) is a reversible direct factor Xa inhibitor used for the treatment and prevention of coagulation in numerous syndromes. There is very limited information available on the transfer of rivaroxaban into human breast milk. Case Report: This study determined the drug concentration-time profile of rivaroxaban in milk samples collected from two lactating mothers consuming 15 mg twice daily. After 21 days, each mother transitioned to 20 mg once daily. Levels in milk were measured using liquid chromatography mass spectrometry and analysis was done for both dosages. The maximum concentration of rivaroxaban observed for the 15 mg dose was 0.3 ± 0.02 µg/mL and that for the 20 mg dose was 0.26 ± 0.01 µg/mL. The relative infant dose (RID) was calculated to be 5% and 4%, respectively. Discussion: This relatively low infant dose is probably explained by the high plasma protein binding of rivaroxaban and its subsequent poor penetration into human milk. The results indicate that rivaroxaban receded to minimum concentration over a period of 12 hours. Conclusions: In these two cases, we found the levels of rivaroxaban in milk to be quite low, and the RID to be 5% of the maternal dose. Although the levels detected were low, rivaroxaban does transfer into breast milk. Caution should be exercised until further studies are conducted and report the safety profile of rivaroxaban in breastfeeding infants.