mTORC2 mediates structural plasticity in distal nociceptive endings that contributes to pain hypersensitivity following inflammation.

The encoding of noxious stimuli into action potential firing is largely mediated by nociceptive free nerve endings. Tissue inflammation, by changing the intrinsic properties of the nociceptive endings, leads to nociceptive hyperexcitability and thus to the development of inflammatory pain. Here, we showed that tissue inflammation-induced activation of the mammalian target of rapamycin complex 2 (mTORC2) triggers changes in the architecture of nociceptive terminals and leads to inflammatory pain. Pharmacological activation of mTORC2 induced elongation and branching of nociceptor peripheral endings and caused long-lasting pain hypersensitivity. Conversely, nociceptor-specific deletion of the mTORC2 regulatory protein rapamycin-insensitive companion of mTOR (Rictor) prevented inflammation-induced elongation and branching of cutaneous nociceptive fibers and attenuated inflammatory pain hypersensitivity. Computational modeling demonstrated that mTORC2-mediated structural changes in the nociceptive terminal tree are sufficient to increase the excitability of nociceptors. Targeting mTORC2 using a single injection of antisense oligonucleotide against Rictor provided long-lasting alleviation of inflammatory pain hypersensitivity. Collectively, we showed that tissue inflammation-induced activation of mTORC2 causes structural plasticity of nociceptive free nerve endings in the epidermis and inflammatory hyperalgesia, representing a therapeutic target for inflammatory pain.

Ephrin-A2 and ephrin-A5 guide contralateral targeting but not topographic mapping of ventral cochlear nucleus axons.

BACKGROUND: In the auditory brainstem, ventral cochlear nucleus (VCN) axons project to the contralateral, but not ipsilateral, medial nucleus of trapezoid body (MNTB), terminating in the calyx of Held. Dorsal VCN neurons, representing high frequencies, synapse with medial MNTB neurons, while low frequency-coding ventral VCN neurons synapse with lateral MNTB neurons, reflecting tonotopic organization. The mechanisms that ensure strictly contralateral targeting and topographic ordering are incompletely understood. Here we examined the roles of ephrin-A signaling in both types of targeting. RESULTS: Ephrin-A2 and ephrin-A5 are expressed in VCN cells during late embryonic and early postnatal development. At these ages ephrin-A2 is expressed in axons surrounding MNTB and ephrin-A5 is expressed in MNTB principal neurons. Ephrin-A2/A5 double knockout mice displayed axon targeting errors in which VCN axons project to MNTB on both sides of the brainstem, where they terminate in calyceal endings. Ephrin-A2 and ephrin-A5 single knockout mice showed a similar phenotype. In contrast to effects on contralateral targeting, ephrin-A2/A5 double knockout mice showed no defects in formation of tonotopically ordered projections from VCN to MNTB. CONCLUSIONS: These findings demonstrate that distinct mechanisms regulate targeting of VCN axons to the contralateral MNTB and targeting to appropriate tonotopic locations. Ephrin-A signaling plays a similar role to ephrin-B signaling in the VCN-MNTB pathway, where both classes normally prevent formation of calyceal projections to ipsilateral MNTB. These classes may rely in part on common signaling pathways.

Psychosocial factors are the most common contraindications for antiviral therapy at initial evaluation in veterans with chronic hepatitis C.

GOALS: To understand the degree to which psychosocial factors were preventing veterans with chronic hepatitis C virus from being eligible for antiviral treatment. BACKGROUND: Nearly 2% of the US population is infected with hepatitis C. Antiviral treatment requires substantial adherence despite challenging side effects. Psychosocial factors, including depression and substance abuse, are clinically recognized contraindications for antiviral treatment. STUDY: At the Houston Veterans Affairs Medical Center HCV Clinic, we prospectively gathered medical and psychosocial data, as well as treatment disposition data, for consecutively referred patients who had screened positive for hepatitis C by enzyme-linked immunosorbent assay serology. RESULTS: Of the 697 patients referred from September 2000 to May 2001, 580 had chronic hepatitis C. The mean age was 51 years, and 99% were men. Psychosocial contraindications prevented hepatitis C antiviral treatment from being started for 406 (70.0%) patients. These contraindications included alcohol abuse (124, 21.4%), substance abuse (21, 3.6%), and depression (93, 16.0%). Among the medical contraindications were end-stage liver disease (34, 5.9%) and poorly controlled diabetes mellitus (20, 3.4%). CONCLUSION: Overall, our experience was that a significant portion of hepatitis C patients could not initially be started on antiviral treatment due to psychosocial factors. To make these patients eligible for treatment, future studies of multidisciplinary interventions are required.