Publications

We hypothesized that TRPV4, a member of the transient receptor family of ion channels, functions as a sensory transducer for osmotic stimulus-induced nociception. We found that, as expected for a transducer molecule, TRPV4 protein is transported in sensory nerve distally toward the peripheral nerve endings. In vivo single-fiber recordings in rat showed that hypotonic solution activated 54% of C-fibers, an effect enhanced by the hyperalgesic inflammatory mediator prostaglandin E2. This osmotransduction causes nociception, since administration of a small osmotic stimulus into skin sensitized by PGE2 produced pain-related behavior. Antisense-induced decrease in expression of TRPV4 confirmed that the channel is required for hypotonic stimulus-induced nociception. Thus, we conclude that TRPV4 can function as an osmo-transducer in primary afferent nociceptive nerve fibers. Because this action is enhanced by an inflammatory mediator, TRPV4 may be important in pathological states and may be an attractive pharmacological target for the development of novel analgesics.

In humans, kappa agonist-antagonist opioids such as nalbuphine have been proposed to produce both analgesia and anti-analgesia by acting at distinct receptors. The anti-analgesia appears to be greater in men, which may contribute to the greater nalbuphine analgesia observed in women. Kappa agonist-antagonists are also known to produce sexually dimorphic antinociception in nonhuman species but are generally more potent in males; anti-analgesia has not been reported in animals. The aim of the present study was to determine if nalbuphine anti-analgesia can be detected in the rat. Since nalbuphine anti-analgesia is more sensitive to naloxone antagonism than its analgesic effect, low doses of naloxone were combined with nalbuphine. Using the Randall-Selitto paw-withdrawal test, nalbuphine (0.5-10 mg/kg) induced dose-dependent antinociception in the rat. The antinociceptive effect of nalbuphine (0.5 or 1 mg/kg) was not enhanced by lower doses of naloxone but was antagonized by higher doses. These data do not support the hypothesis that the naloxone-sensitive anti-analgesic effect of nalbuphine observed in humans is present in the rat and could explain, at least in part, the opposite direction of the sex differences for kappa agonist-antagonist opioid analgesia observed in these two species.

Viral protein R (Vpr) of human immunodeficiency virus, type 1 (HIV-1) is the major virion-associated accessory protein that affects a number of biological functions in the retroviral life cycle, including promotion of the transport of the preintegration complex into the nucleus and the induction of G2 host cell cycle arrest. Our recent investigation of the conformational heterogeneity of the proline residues in the N terminus of Vpr suggested a functional interaction between Vpr and a host peptidylprolyl cis/trans isomerase (PPIase) that might regulate the cis/trans interconversion of the imidic bond within the conserved proline residues of Vpr in vivo. Using surface plasmon resonance spectroscopy, Far Western blot, and pulldown experiments a physical interaction of Vpr with the major host PPIase cyclophilin A (CypA) is now demonstrated. The interaction domain involves the N-terminal region of Vpr including an essential role for proline in position 35. The CypA inhibitor cyclosporin A and non-immunosuppressive PPIase inhibitors such as NIM811 and sanglifehrin A block expression of Vpr without affecting pre- or post-translational events such as transcription, intracellular transport, or virus incorporation of Vpr. Similarly to CypA inhibition, Vpr expression is also reduced in HIV-1 infected CypA-/- knock-out T cells. This study thus shows that in addition to the interaction between CypA and HIV-1 capsid occurring during early steps in virus replication, CypA is also important for the de novo synthesis of Vpr and that in the absence of CypA activity, the Vpr-mediated cell cycle arrest is completely lost in HIV-1-infected T cells.