Bi-phasic intensity-dependent opioid-mediated neural amplitude changes in the chinchilla cochlea: partial blockade by an N-Methyl-D-Aspartate (NMDA)-receptor antagonist.

Dynorphins, glutamate, and glutamate-sensitive N-Methyl-D-Aspartate (NMDA) receptors exist in the mammalian cochlea. Dynorphins produce neural excitation and excitotoxic effects in the spinal cord through a kappa-opioid facilitation of NMDA receptor-sensitivity to glutamate. The kappa-opioid receptor drug agonists N-dimethylallyl-normetazocine [(-)-pentazocine (50 mmol)] and trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide [U-50488H (100 mmol)] were administered across the cochlear round window membrane in the chinchilla. Each drug produced significant post-baseline amplitude changes in the click-evoked auditory nerve compound action potential. Amplitude changes at threshold amounted to increases in sensitivity that ranged from 4-8 decibels, measured in sound pressure level (dB SPL). The large neural amplitude increases at threshold were accompanied by progressively smaller amplitude changes at 5 and 10 dB above threshold (dB SL). However, at stimulus intensities > or =20 dB SL, post-baseline neural amplitudes were suppressed to levels below baseline and control values. These bi-phasic intensity-dependent neural amplitude changes have never before been observed following i.v. administered (-)-pentazocine in this species. Finally, the bi-phasic neural amplitude changes in U-50488H-treated (100 mmol) animals were partially blocked (except at 20 dB SL), following a round window pre-treatment with the NMDA receptor drug antagonist, dizocilpine hydrogen maleate [(+)-MK-801 (8 mmol)]. Our data suggests that endogenous dynorphins within lateral efferent olivocochlear neurons differentially modulate auditory neural excitation, possibly through cochlear NMDA receptors and glutamate. The role played by lateral efferent opioid neuromodulation at cochlear NMDA receptors, is discussed.

Tissue-type plasminogen activator is upregulated in metastatic breast cancer cells exposed to insulin-like growth factor-I.

The insulin-like growth factor (IGF) system plays an important role in breast tumorigenesis. Breast cancer cells express the type I IGF receptor (IGF-IR) and respond to IGFs in the environment. Tissue-type plasminogen activator (tPA) has been shown to be associated with neoplastic transformation and the invasive phenotype for highly aggressive tumors; however, its role in breast cancer remains unclear. We asked whether there is a relationship between the IGF system and tPA in estrogen receptor-negative breast cancer cells that could contribute to invasion. When MDA-MB-435s breast cancer cells were exposed to IGF-I, tPA messenger RNA (mRNA) was upregulated in a time-dependent fashion. Tissue-type plasminogen activator protein accumulation was also increased in a similar manner. The invasiveness of MDA-MB-435s cells was enhanced in the presence of IGF-I. When the MDA-MB-435s cells were stably transfected with an antisense IGF-IR expression construct, the transfectants expressed high levels of IGF-IR antisense, dramatically reduced levels of endogenous IGF-IR, and a decrease in relative staining intensity for IGF-IR protein. A marked suppression in tPA mRNA expression occurred in MDA-MB-435s cells accompanying inhibition of IGF-IR. When cells carrying the antisense IGF-IR expression construct were exposed to IGF-I, tPA protein accumulation was significantly lower than that of control transfected cells. To our knowledge, this study is the first to show a relationship between the IGF system and tPA. Strategies that target the IGF/tPA pathway could provide alternative treatments for patients with certain types of metastatic breast cancer.