Over the last several years, compelling evidence has accumulated indicating that central hyperactive states resulting from neuronal plastic changes within the spinal cord play a critical role in hyperalgesia associated with nerve injury and inflammation. Such neuronal plastic changes may involve activation of central nervous system excitatory amino acid (EAA) receptors, subsequent intracellular cascades including protein kinase C translocation and activation as well as nitric oxide production, leading to the functional modulation of receptor-ion channel complexes. Similar EAA receptor-mediated cellular and intracellular mechanisms have now been implicated in the development of tolerance to the analgesic effects of morphine, and a site of action involved in both hyperalgesia and morphine tolerance is likely to be in the superficial laminae of the spinal cord dorsal horn. These observations suggest that hyperalgesia and morphine tolerance, two seemingly unrelated phenomena, may be interrelated by common neural substrates that interact at the level of EAA receptor activation and related intracellular events. This view is supported by recent observations showing that thermal hyperalgesia develops when animals are made tolerant to morphine antinociception and that both hyperalgesia and reduction of the antinociceptive effects of morphine occur as a consequence of peripheral nerve injury. The demonstration of interrelationships between neural mechanisms underlying hyperalgesia and morphine tolerance may lead to a better understanding of the neurobiology of these two phenomena in particular and pain in general. This knowledge may also provide a scientific basis for improved pain management with opiate analgesics.

Research during the past decade has revealed the existence of neural systems that modulate pain transmission. Much of this work has focused on the role of endogenous opiate systems, but recent research indicates the involvement of nonopiate mechanisms as well. In this article, we present data demonstrating that opiate and nonopiate analgesia systems can be selectively activated by different environmental manipulations and describe the neural circuitry involved. Both neural and hormonal pathways and both opiate and nonopiate substances play roles in the complex modulation of pain transmission. The existence and description of these modulatory mechanisms have important clinical implications for the treatment of pain.

In a rat model of morphine tolerance, we examined the hypotheses that thermal hyperalgesia to radiant heat develops in association with the development of morphine tolerance and that both the development and expression of thermal hyperalgesia in morphine-tolerant rats are mediated by central NMDA and non-NMDA receptors and subsequent protein kinase C (PKC) activation. Tolerance to the analgesic effect of morphine was developed in rats utilizing an intrathecal repeated treatment regimen. The development of morphine tolerance and thermal hyperalgesia was examined by employing the tail-flick test and paw- withdrawal test, respectively. Intrathecal MK 801 (an NMDA receptor antagonist), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; a non-NMDA receptor antagonist), or GM1 ganglioside (an intracellular PKC inhibitor) treatment was given to examine the effects of these agents on the development and expression of thermal hyperalgesia in morphine- tolerant rats. Tolerance to the analgesic effect of morphine was reliably developed in rats following once daily intrathecal (onto the lumbosacral spinal cord) injection of 10 micrograms of morphine sulfate for 8 consecutive days as demonstrated by the decreased analgesia following morphine administration on day 8 as compared to that on day 1. In association with the development of morphine tolerance, thermal hyperalgesia to radiant heat developed in these same rats. Paw- withdrawal latencies were reliably decreased in morphine-tolerant rats as compared to nontolerant (saline) controls when tested on day 8 before the last morphine treatment and on day 10 (i.e., 48 hr after the last morphine treatment). The coincident development of morphine tolerance and thermal hyperalgesia was potently prevented by intrathecal coadministration of morphine with MK 801 (10 nmol) or GM1 (160 nmol), and partially by CNQX (80 nmol). MK 801 (5, 10 nmol, not 2.5 nmol) and CNQX (80, 160 nmol, not 40 nmol), but not GM1 (160 nmol), also reliably reversed thermal hyperalgesia in rats rendered tolerant to morphine when tested 30 min after each drug treatment on day 10 (48 hr after the last morphine treatment). The data indicate that thermal hyperalgesia develops in association with the development of morphine tolerance and that the coactivation of central NMDA and non-NMDA receptors is crucial for both the development and expression of thermal hyperalgesia in morphine-tolerant rats. Furthermore, intracellular PKC activation plays a critical role in the development of thermal hyperalgesia in morphine-tolerant rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Compelling evidence has accumulated over the last several years from our laboratory, as well as others, indicating that central hyperactive states resulting from neuronal plastic changes within the spinal cord play a critical role in hyperalgesia associated with nerve injury and inflammation. In our laboratory, chronic constriction injury of the common sciatic nerve, a rat model of neuropathic pain, has been shown to result in activation of central nervous system excitatory amino acid receptors and subsequent intracellular cascades including protein kinase C translocation and activation, nitric oxide production, and nitric oxide-activated poly(ADP ribose) synthetase activation. Similar cellular mechanisms also have been implicated in the development of tolerance to the analgesic effects of morphine. A recently observed phenomenon, the development of ''dark neurons,'' is associated with both chronic constriction injury and morphine tolerance. A site of action involved in both hyperalgesia and morphine tolerance is in the superficial laminae of the spinal cord dorsal horn. These observations suggest that hyperalgesia and morphine tolerance may be interrelated at the level of the superficial laminae of the dorsal horn by common neural substrates that interact at the level of excitatory amino acid receptor activation and subsequent intracellular events. The demonstration of interrelationships between neural mechanisms underlying hyperalgesia and morphine tolerance may lead to a better understanding of the neurobiology of these two phenomena in particular and pain in general. This knowledge may also provide a scientific basis for improved pain management with opiate analgesics.A number of studies, both from our laboratory as well as others, indicate that central hyperactive states resulting from neuronal plastic changes within the spinal cord play a critical role in hyperalgesia associated with nerve injury and inflammation. We have recently shown in a rat model of neuropathic pain that chronic constrictive injury (CCI) of the common sciatic nerve can result in activation of central nervous system excitatory amino acid receptors and subsequent intracellular cascades including protein kinase C translocation and activation, nitric oxide (NO) production, and NO-activated poly(ADP ribose) synthetase (PARS) activation. Similar cellular mechanisms also have been implicated in the development of tolerance to the analgesic effects of morphine. Of particular interest is that morphological changes in the spinal cord dorsal horn, the development of so called ''dark neurons,'' are associated with both CCI and morphine tolerance. A site of action involved in both hyperalgesia and morphine tolerance has also been shown to be in the superficial laminae of the spinal cord dorsal horn. We will first summarize recent evidence indicating central mechanisms of hyperalgesia and morphine tolerance. The main focus of this article will be on the recent development in our understanding of the involvement of PARS activation in central...

A new realization of the International Celestial Reference Frame (ICRF) is presented based on the work achieved by a working group of the International Astronomical Union (IAU) mandated for this purpose. This new realization follows the initial realization of the ICRF completed in 1997 and its successor, ICRF2, adopted as a replacement in 2009. The new frame, referred to as ICRF3, is based on nearly 40 years of data acquired by very long baseline interferometry at the standard geodetic and astrometric radio frequencies (8.4 and 2.3 GHz), supplemented with data collected at higher radio frequencies (24 GHz and dual-frequency 32 and 8.4 GHz) over the past 15 years. State-of-the-art astronomical and geophysical modeling has been used to analyze these data and derive source positions. The modeling integrates, for the first time, the effect of the galactocentric acceleration of the solar system (directly estimated from the data) which, if not considered, induces significant deformation of the frame due to the data span. The new frame includes positions at 8.4 GHz for 4536 extragalactic sources. Of these, 303 sources, uniformly distributed on the sky, are identified as “defining sources” and as such serve to define the axes of the frame. Positions at 8.4 GHz are supplemented with positions at 24 GHz for 824 sources and at 32 GHz for 678 sources. In all, ICRF3 comprises 4588 sources, with three-frequency positions available for 600 of these. Source positions have been determined independently at each of the frequencies in order to preserve the underlying astrophysical content behind such positions. They are reported for epoch 2015.0 and must be propagated for observations at other epochs for the most accurate needs, accounting for the acceleration toward the Galactic center, which results in a dipolar proper motion field of amplitude 0.0058 milliarcsecond yr−1 (mas yr−1). The frame is aligned onto the International Celestial Reference System to within the accuracy of ICRF2 and shows a median positional uncertainty of about 0.1 mas in right ascension and 0.2 mas in declination, with a noise floor of 0.03 mas in the individual source coordinates. A subset of 500 sources is found to have extremely accurate positions, in the range of 0.03–0.06 mas, at the traditional 8.4 GHz frequency. Comparing ICRF3 with the recently released Gaia Celestial Reference Frame 2 in the optical domain, there is no evidence for deformations larger than 0.03 mas between the two frames, in agreement with the ICRF3 noise level. Significant positional offsets between the three ICRF3 frequencies are detected for about 5% of the sources. Moreover, a notable fraction (22%) of the sources shows optical and radio positions that are significantly offset. There are indications that these positional offsets may be the manifestation of extended source structures. This third realization of the ICRF was adopted by the IAU at its 30th General Assembly in August 2018 and replaced the previous realization, ICRF2, on January 1, 2019.

Stimulation at several mesencephalic and diencephalic sites abolished responsiveness to intense pain in rats while leaving responsiveness to other sensory modes relatively unaffected. The peripheral field of analgesia was usually restricted to one-half or to one quadrant of the body, and painful stimuli applied outside this field elicited a normal reaction. Analgesia outlasted stimulation by up to 5 minutes. Most electrode placements that produced analgesia also supported self-stimulation. One placement supported self-stimulation only in the presence of pain.

Oral doses of dextromethorphan (DM), a common cough suppressant and N-methyl-D-aspartate (NMDA) receptor antagonist, and their vehicle control were given on a double-blind basis to normal volunteer human subjects who rated intensities of first and second pain in response to repeated painful electric shocks and repeated 52 degrees C heat pulses. Doses of 30 and 45 mg, but not 15 mg, were effective in attenuating temporal summation of second pain, a psychophysical correlate of temporal summation of C afferent-mediated responses of dorsal horn nociceptive neurons, termed 'wind-up'. By contrast, neither first nor second pain evoked by the first stimulus in a train of stimuli were affected by any of these doses of DM. These results further confirm temporal summation of second pain as a psychophysical correlate of wind-up by providing evidence that DM selectively reduces temporal summation of second pain, as has been shown for wind-up.

Recent evidence suggests that hyperalgesia and morphine tolerance, two seemingly unrelated phenomena, have in common certain neural substrates such as activation of the N-methyl-D-aspartate (NMDA) receptor and the subsequent intracellular activation of protein kinase C and nitric oxide. Should common cellular elements be involved in hyperalgesia and morphine tolerance, these cellular and intracellular commonalities might be expected to result in interactions between these two phenomena. Indeed, our previous studies have shown that thermal hyperalgesia develops when animals are made tolerant to the antinociceptive effects of morphine. In this study, we examined the hypothesis that reduction of morphine antinociception occurs following unilateral ligation of the rats's sciatic nerve, a procedure which produces symptoms of a neuropathic pain syndrome including thermal hyperalgesia. When tested using the paw-withdrawal test on day 8 (D8) after either nerve ligation or sham operation, a single intrathecal treatment with 10 micrograms morphine sulfate (30 min after administration) produced significant antinociception in sham-operated rats but not in nerve-injured ones. These results also were obtained when thermal hyperalgesia was reversed in nerve-injured rats by the non-competitive NMDA receptor antagonist MK-801. Consistently, 8 days after sciatic nerve ligation but not after a sham operation, an approximately 6-fold rightward shift occurred in the morphine antinociceptive dose-response curve. This rightward shift of the morphine antinociceptive dose-response curve did not occur at 24 h after either nerve ligation or sham operation. In addition, once daily treatment with 10 nmol MK-801 from D2 to D7 after nerve ligation prevented both the development of thermal hyperalgesia and the rightward shift of the morphine antinociceptive dose-response curve on D8. The results indicate that the antinociceptive effects of morphine are reduced in nerve-injured rats in the absence of daily exposure to morphine and that the NMDA receptor activation may have a critical role in mechanisms of this phenomenon. These data provide further evidence indicating that interactions do occur between neural mechanisms underlying thermal hyperalgesia and morphine tolerance.