The Yin and Yang of pain: variability in formalin test nociception and morphine analgesia produced by the Yin Yang 1 transcription factor gene.

We recently observed a reliable phenotypic difference in the inflammatory pain sensitivity of a congenic mouse strain compared to its background strain. By constructing and testing subcongenic strains combined with gene-expression assays, we provide evidence for the candidacy of the Yy1 gene - encoding the ubiquitously expressed and multifunctional Yin Yang 1 transcription factor - as responsible. To confirm this hypothesis, we used a Cre/lox strategy to produce mutant mice in which Yy1 expression was ablated in Nav 1.8-positive neurons of the dorsal root ganglion. These mutants also displayed reduced inflammatory pain sensitivity on the formalin test. Further testing of pain-related phenotypes in these mutants revealed robustly increased sensitivity to systemic and spinal (but not supraspinal) morphine analgesia, and greatly increased endogenous (swim stress-induced) opioid analgesia. None of the known biological roles of Yin Yang 1 were suggestive of such a phenotype, and thus a novel player in pain modulatory systems has been identified.

The effect of genotype on sensitivity to electroacupuncture analgesia.

Individual differences in sensitivity to pain and analgesia are well appreciated, and increasing evidence has pointed towards a role of inherited genetic factors in explaining some proportion of such variability. It has long been known by practitioners of acupuncture, an ancient modality of analgesia, that some patients are 'responders' and others 'non-responders.' The present research was aimed at defining the inherited genetic influence on acupuncture analgesia in the mouse, using 10 common inbred strains. Two pairs of metallic needles were inserted into acupoints ST 36 and SP 6, fixed in situ and then connected to the output channel of an electric pulse generator. Electroacupuncture (EA) parameters were set as constant current output (intensity: 1.0-1.5-2.0 mA, 10 min each; frequency: 2 or 100 Hz) with alteration of a positive and negative square wave, 0.3 ms in pulse width. Tail-flick latencies evoked by radiant heat were measured before, during and after EA stimulation. Narrow-sense heritability estimates of 2 and 100 Hz EA were 0.37 and 0.16, respectively. We found that the C57BL/10 strain was the most sensitive, and the SM strain was the least sensitive to both 2 and 100 Hz EA. However, the relative sensitivities of other strains to these two EA frequencies suggested some genetic dissociation between them as well. These results demonstrate a role of inherited genetic factors in EA sensitivity in the mouse, although the low-to-moderate heritability estimates suggest that environmental factors may be of greater importance in predicting who will benefit from this analgesic modality.

Ginsenoside Rf, a trace component of ginseng root, produces antinociception in mice.

Ginseng root, a traditional oriental medicine, contains more than a dozen biologically active saponins called ginsenosides, including one present in only trace amounts called ginsenoside-Rf (Rf). Previously, we showed that Rf inhibits Ca2+ channels in mammalian sensory neurons through a mechanism requiring G-proteins, whereas a variety of other ginsenosides were relatively ineffective. Since inhibition of Ca2+ channels in sensory neurons contributes to antinociception by opioids, we tested for analgesic actions of Rf. We find dose-dependent antinociception by systemic administration of Rf in mice using two separate assays of tonic pain: in the acetic acid abdominal constriction test, the ED50 was 56+/-9 mg/kg, a concentration similar to those reported for aspirin and acetaminophen in the same assay; in the tonic phase of the biphasic formalin test, the ED50 was 129+/-32 mg/kg. Rf failed to affect nociception measured in three assays of acute pain: the acute phase of the formalin test, and the thermal (49 degrees C) tail-flick and increasing-temperature (3 degrees C/min) hot-plate tests. The simplest explanation is that Rf inhibits tonic pain without affecting acute pain, but other possibilities exist. Seeking a cellular explanation for the effect, we tested whether Rf suppresses Ca2+ channels on identified nociceptors. Inhibition was seen on large, but not small, nociceptors. This is inconsistent with a selective effect on tonic pain, so it seems unlikely that Ca2+ channel inhibition on primary sensory neurons can fully explain the behavioral antinociception we have demonstrated for Rf.

Involvement of endogenous orphanin FQ in electroacupuncture-induced analgesia.

Recent studies suggest that the novel opioid peptide orphanin FQ (OFQ) is involved in pain modulation. We found that intracerebroventricular (i.c.v.) administration of OFQ in the rat produced a dose-dependent antagonism of the analgesia induced by 100 Hz electroacupuncture (EA) stimulation as measured in the radiant heat tail-flick assay. Antisense oligonucleotides injected i.c.v. potentiated EA analgesia, presumably by interfering with the expression of the OFQ receptor in brain. These results suggest that endogenous OFQ exerts a tonic antagonistic effect on EA-induced analgesia. No such antagonism was observed when OFQ was injected intrathecally (i.t.). Rather, it appears that spinal OFQ produced a marked analgesic effect and enhanced EA-induced analgesia. These findings are consistent with the experimental results obtained in rats where morphine-induced analgesia is antagonized by i.c.v. OFQ and potentiated by i.t. OFQ.