Search

We report on the spectral cross-calibration results of the Konus-Wind, the Suzaku/WAM, and the Swift/BAT instruments using simultaneously observed gamma-ray bursts (GRBs). This is the first attempt to use simultaneously observed GRBs as a spectral calibration source to understand systematic problems among the instruments. Based on these joint spectral fits, we find that (1) although a constant factor (a normalization factor) agrees within 20% among the instruments, the BAT constant factor shows a systematically smaller value by 10%–20% compared to that of Konus-Wind, (2) there is a systematic trend that the low-energy photon index becomes steeper by 0.1–0.2 and $E_{\rm peak}$becomes systematically higher by 10%–20% when including the BAT data in the joint fits, and (3) the high-energy photon index agrees within 0.2 among the instruments. Our results show that cross-calibration based on joint spectral analysis is an important step to understanding the instrumental effects that could be affecting the scientific results from the GRB prompt emission data.

Previous findings in our laboratory suggested that the M1muscarinic acetylcholine receptor (mAChR) agonist xanomeline exhibits a novel mode of interaction that involves persistent binding to and activation of the M1mAChR, subsequent to extensive washout, as well as a possible insurmountable element. In the present study, we examined this interaction in greater detail, using Chinese hamster ovary cells transfected with the genes for the M1mAChR and neuronal nitric oxide synthase. Pretreatment of cells with xanomeline, followed by extensive washout, resulted in elevated basal levels of neuronal nitric oxide synthase activity that were suppressed by the antagonists atropine or pirenzepine in a concentration-dependent manner. Analysis of the data yielded estimates of Schild slope factors and p KBvalues for the antagonists that were consistent with a model of simple competition between these latter agents and the persistently bound form of xanomeline. The ability of the antagonists to produce parallel dextral shifts of the concentration-response curves to carbachol and xanomeline was also investigated. The interaction between xanomeline and pirenzepine appeared to be insurmountable, but this may have been due to an equilibrium artifact. In contrast, the interaction between xanomeline and atropine conformed to a model of competition, indicating that the mode of interaction of free xanomeline at the M1mAChR is pharmacologically identical with that of the persistently bound form. Radioligand binding studies also showed that the presence of various concentrations of xanomeline had no significant effect on the calculated affinity of atropine or pirenzepine in inhibiting the binding of [3H]N-methylscopolamine. Overall, these findings suggest that the persistent attachment of xanomeline to the M1mAChR does not prevent this agonist from interacting with the classic binding site in a competitive fashion.

This study investigated second messengers formed in response to calcitonin gene-related peptide (CGRP) in primary cultures of neonatal rat spinal cord. CGRP increased the level of cAMP above basal levels (50 pmol/mg protein) over a large range of concentrations. The concentration-response curve had an intermediate plateau at 180 pmol cAMP/mg protein in response to 0.01–0.1 nM CGRP and a maximal plateau of 850 pmol cAMP/mg protein at 300 nM CGRP. The biphasic concentration-response curve (EC50s of 0.7 pM and 22 nM) suggests activation of high- and low-affinity receptors for CGRP. Both neurons and nonneuronal cells contributed to the increase in cAMP formation in response to CGRP. The CGRP receptor blocker, CGRP8–37, inhibited the response to both 1 and 100 nM CGRP, providing additional support for the hypothesis that both high- and low-affinity receptors mediate the formation of cAMP. Only a high concentration of CGRP (1 μM) increased the formation of cGMP, and CGRP had no effect on the formation of inositol phosphates at any of the concentrations tested (0.1–1 μM). These results suggest that CGRP-induced responses in the spinal cord are mediated predominately via the formation of cAMP. The observation that both neurons and nonneuronal cells responded to CGRP indicate that this peptide may have multiple actions in the spinal cord. Synapse 26:235–242, 1997. © 1997 Wiley-Liss Inc.

Hyperalgesia is a characteristic of inflammation and is mediated, in part, by an increase in the excitability of spinal neurons. Although substance P does not appear to mediate fast synaptic events that underlie nociception in the spinal cord, it may contribute to the hyperalgesia and increased excitability of spinal neurons during inflammation induced by complete Freund's adjuvant. We examined the role of endogenous substance P in changes in the excitability of spinal neurons during adjuvant-induced, peripheral inflammation by determining the effect of a selective NK1receptor antagonist (RP67580) on the nociceptive flexor reflex in adult rats. Experiments were conducted 2 or 3 days after injection of adjuvant. Animals exhibited moderate thermal hyperalgesia at this time. The flexor reflex was evoked by electrical stimulation of the sural nerve and was recorded in the ipsilateral hamstring muscles. The flexor reflex ipsilateral to the inflamed hindpaw was enhanced approximately two-fold compared to the flexor reflex evoked in untreated animals as determined by the number of potentials and the duration of the reflex. The enhanced reflex in adjuvant-treated animals was most likely due to an increase in the excitability of spinal interneurons because short-latency activity in the hamstring muscles did not differ between untreated animals and adjuvant-treated animals following electrical stimulation of the L5dorsal root or the nerve innervating the muscle with a stimulus that was 1.3–1.5 times the threshold for excitation of A-fibers. Intrathecal administration of RP67580 (2.3 and 6.8 nmol) attenuated the flexor reflex evoked in adjuvant-treated animals, but had no effect in untreated animals. Intravenous or intraplantar injection of RP67580 (6.8 nmol) did not affect the flexor reflex in adjuvant-treated animals indicating a spinal action of the drug following intrathecal administration. RP68651, the enantiomer of RP67580, was without effect at doses up to 6.8 nmol, indicating that the effects of comparable doses of RP67580 were due to an action of the drug at NK1receptors. However, intrathecal administration of 23 nmol of both drugs attenuated the reflex in adjuvant-treated and control animals indicating that effects of RP67580 at this dose were not mediated entirely by its action at NK1receptors. Overall, these data suggest that endogenous substance P has a role in the increased excitability of spinal interneurons observed during persistent inflammation and support the hypothesis that substance P released in the spinal cord contributes to the hyperalgesia that accompanies adjuvant-induced persistent, peripheral inflammation.

This study investigated second messengers formed in response to calcitonin gene‐related peptide (CGRP) in primary cultures of neonatal rat spinal cord. CGRP increased the level of cAMP above basal levels (50 pmol/mg protein) over a large range of concentrations. The concentration‐response curve had an intermediate plateau at 180 pmol cAMP/mg protein in response to 0.01–0.1 nM CGRP and a maximal plateau of 850 pmol cAMP/mg protein at 300 nM CGRP. The biphasic concentration‐response curve (EC50s of 0.7 pM and 22 nM) suggests activation of high‐ and low‐affinity receptors for CGRP. Both neurons and nonneuronal cells contributed to the increase in cAMP formation in response to CGRP. The CGRP receptor blocker, CGRP8–37, inhibited the response to both 1 and 100 nM CGRP, providing additional support for the hypothesis that both high‐ and low‐affinity receptors mediate the formation of cAMP. Only a high concentration of CGRP (1 μM) increased the formation of cGMP, and CGRP had no effect on the formation of inositol phosphates at any of the concentrations tested (0.1–1 μM). These results suggest that CGRP‐induced responses in the spinal cord are mediated predominately via the formation of cAMP. The observation that both neurons and nonneuronal cells responded to CGRP indicate that this peptide may have multiple actions in the spinal cord. Synapse 26:235–242, 1997. © 1997 Wiley‐Liss Inc.