Spinal cord neuroplasticity following repeated opioid exposure and its relation to pathological pain.

Convincing evidence has accumulated that indicates neuroplastic changes within the spinal cord in response to repeated exposure to opioids. Such neuroplastic changes occur at both cellular and intracellular levels. It has been generally acknowledged that the activation of N-methyl-D-aspartate (NMDA) receptors plays a pivotal role in the development of neuroplastic changes following repeated opioid exposure. Intracellular cascades can also be activated subsequent to NMDA receptor activation. In particular, protein kinase C has been shown to be a key intracellular element that contributes to the behavioral manifestation of neuroplastic changes. Moreover, interactions between NMDA and opioid receptors can lead to potentially irreversible degenerative neuronal changes in the spinal cord in association with the development of opioid tolerance. Interestingly, similar cellular and intracellular changes occur in the spinal cord following peripheral nerve injury. These findings indicate that interactions exist in the spinal cord neural structures between two seemingly unrelated conditions-chronic opioid exposure and a pathological pain state. These observations may help understand mechanisms of chemical intolerance and multiple chemical sensitivity as well as have significant clinical implications in pain management with opioid analgesics.

Acupuncture: an evidence-based review of the clinical literature.

This chapter reviews the experimental literature on the effects of acupuncture treatment. The review covers the 14 medical conditions for which the National Institutes of Health Acupuncture Consensus Development Panel (NIHCDP) concluded that acupuncture either is effective (2 conditions) or may be useful (12 conditions). My conclusions partially support those of the NIHCDP. There is evidence that acupuncture is effective for the treatment of postoperative and chemotherapy-induced nausea and vomiting. Also, some data indicate that acupuncture may be useful for headache, low back pain, alcohol dependence, and paralysis resulting from stroke (4 of the 12 conditions for which the NIHCDP found that acupuncture may be useful). For most of the remaining conditions, there is little evidence that acupuncture is either effective or ineffective. It is recommended that workers in the field design double blind, sham controlled trials using adequate acupuncture treatment regimens, with specific hypotheses, and sample sizes sufficient to allow both positive and negative conclusions.

Two distinctive antinociceptive systems in rats with pathological pain.

A common obstacle in clinical management of pathological pain is the poor response to opioid analgesics. We now report that delta9-tetrahydrocannabinol (delta9-THC)-induced antinociception remained effective in rats with pathological pain. The selective central cannabinoid receptor antagonist SR141716A, but not the generic opioid receptor antagonist naloxone, blocked the delta9-THC antinociception. Moreover, there is no cross-tolerance between the antinociceptive effects of morphine and delta9-THC in pathological pain states. The results indicate that delta9-THC antinociception is both effective and independent of opioid receptors in rats with pathological pain. Thus, the cannabinoid analgesic system may be superior to opioids in alleviating intractable pathological pain syndromes.

NMDA-receptor antagonists and opioid receptor interactions as related to analgesia and tolerance.

A model proposing that N-methyl-D-aspartate (NMDA) receptor and opioid receptor mechanisms overlap and interact within the same dorsal horn nociceptive neurons makes several predictions. First, hyperalgesia should be associated with opioid tolerance. Second, both hyperalgesia and tolerance to opioid-analgesia should be blocked by an NMDA-receptor antagonist. Results from our laboratory and others support these predictions and point to several clinical implications. One is that, in addition to preventing tolerance and dependence, combining NMDA-receptor antagonists with both opioid and nonopioid analgesics may increase their analgesic potency. Preclinical animal studies demonstrate these advantages and underscore the practicality of the combined administration of nontoxic NMDA-receptor antagonists with various types of analgesic drugs.

Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions.

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.

Antinociceptive tolerance to the mu-opioid agonist DAMGO is dose-dependently reduced by MK-801 in rats.

Morphine has been used in previous studies that investigate interactions between the spinal cord mu-opioid and N-methyl-D-aspartate (NMDA) receptors in mechanisms of antinociceptive tolerance. Although morphine acts primarily on the mu-receptor, it also activates other subtypes of opioid receptors. In the present study, the selective mu-opioid agonist, D-Ala2-N-Me-Phe4,Gly-ol5-enkephalin (DAMGO), was used to further test the hypothesis. Repeated intrathecal (i.t.) administration of 6 microg DAMGO (twice daily) in rats for 7 days resulted in an approximately 17-fold rightward shift of the cumulative dose-response curve (the tail-flick test) on Day 8 compared to that on Day 1. This rightward shift of the dose-response curve was prevented by the i.t. co-administration with DAMGO of the NMDA receptor antagonist MK-801 (10 = 5 > 2.5 >> 1.25 nmol > saline). Further, a lower dose range of MK-801 (2.5 > 1.25 nmol > 0.625 > 0.313 = saline) was effective to prevent the antinociceptive tolerance to a lower dose (1.5 microg) of DAMGO using the same i.t. administration regimen. Thus, the present results provide further evidence supporting a cellular and intracellular model of opioid tolerance involving interactions between the mu-opioid and the NMDA receptors in the spinal cord.

The inhibition of nitric oxide-activated poly(ADP-ribose) synthetase attenuates transsynaptic alteration of spinal cord dorsal horn neurons and neuropathic pain in the rat.

Transsynaptic alteration of spinal cord dorsal horn neurons characterized by hyperchromatosis of cytoplasm and nucleoplasm (so-called 'dark' neurons) occurs in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the common sciatic nerve. The incidence of dark neurons in CCI rats has been proposed to be mediated by glutamate-induced neurotoxicity. In the present study, we examined whether the inhibition of the nitric oxide (NO)-activated poly(ADP-ribose) synthetase (PARS), a nuclear enzyme critical to glutamate-induced neurotoxicity, would both reduce the incidence of dark neurons and attenuate behavioral manifestations of neuropathic pain in CCI rats. Dark neurons were observed bilaterally (with ipsilateral predominance) within the spinal cord dorsal horn, particularly in laminae I-II, of rats 8 days after unilateral sciatic nerve ligation as compared to sham operated rats. The number of dark neurons in the dorsal horn was dose-dependently reduced in CCI rats receiving once daily intrathecal (i.t.) treatment with the PARS inhibitor benzamide (200 or 400 nmol, but not 100 nmol benzamide or saline) for 7 days. Consistent with the histological improvement, thermal hyperalgesia, mechanical hyperalgesia, and low threshold mechano-allodynia also were reliably reduced in CCI rats treated with either 200 or 400 nmol benzamide. Neither dark neurons nor neuropathic pain behaviors were reliably affected by i.t. administration of either 800 nmol novobiocin (a mono(ADP-ribose) synthetase) or 800 nmol benzoic acid (the backbone structure of benzamide), indicating a selective effect of benzamide. Intrathecal treatment with an NO synthase inhibitor NG-nitro-L-arginine methyl ester (40 nmol, but not its inactive D-isomer) utilizing the same benzamide treatment regimen resulted in similar reductions of both dark neurons and neuropathic pain behaviors in CCI rats. These results provide, for the first time, in vivo evidence indicating that benzamide is neuroprotective and that the PARS-mediated transsynaptic alteration of spinal cord dorsal horn neurons contributes to behavioral manifestations of neuropathic pain in CCI rats. These observations may have general implications beyond treatment of neuropathic pain in that PARS-mediated neuronal alterations may play a significant role in glutamate-mediated neurotoxicity under many other circumstances.

Effects of the combined oral administration of NSAIDs and dextromethorphan on behavioral symptoms indicative of arthritic pain in rats.

The effects of combined single oral treatments with non-steroidal anti-inflammatory drugs (NSAIDs) and the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dextromethorphan (DM) on arthritic pain were examined in a rat model of adjuvant-induced arthritis. Although 12.5-100 mg/kg doses of DM alone produced no reliable effects, treatments with ibuprofen (IB, 50 and 100 mg/kg but not 12.5 or 25 mg/kg) produced mild analgesia in arthritic rats as determined using the Randall-Sellito test. IB showed a dose-response relationship which appeared to plateau at doses of 50 and 100 mg/kg. Adding 50 mg/kg DM to each IB dose resulted in significantly greater analgesic activity than IB alone at doses of 25, 50 and 100 mg/kg. A similar interaction between 50 mg/kg DM and 50 mg/kg IB occurred with respect to spontaneous pain behavior. Adding 25 mg/kg DM to 25 mg/kg IB likewise increased analgesia as measured by both the Randall-Sellito and spontaneous pain behavior tests (both P < 0.05). Five more NSAIDs were evaluated using the Randall-Sellito test, which included naproxen (NP), piroxicam (PIR), etodolac (ET), diclofenac (DC), and ketorolac (KE). For all six NSAIDS, the addition of 50 mg/kg DM reliably increased their analgesic potency, as indicated by reliable increases in previously effective NSAID doses (all six NSAIDs) as well as previously ineffective NSAID doses (IB, NP, DC, and PIR). These data demonstrate that DM greatly potentiates the analgesic activity of IB, DC, NP, PIR, ET, and KT and increases the peak effect over the NSAIDs alone. Similiar to DM's previously demonstrated enhancement of opioid analgesia in acute pain, the combination of DM and an NSAID may represent a novel analgesic approach to improved management of arthritic pain.

Oral administration of dextromethorphan prevents the development of morphine tolerance and dependence in rats.

Combined oral administration of morphine sulfate (MS) and the over-the-counter antitussive drug and N-methyl-D-aspartate receptor antagonist dextromethorphan (DM) prevented the development of tolerance to the antinociceptive effects of MS (15, 24, or 32 mg/kg) in rats. This combined oral treatment regimen also attenuated signs of naloxone-precipitated physical dependence on morphine in the same rats. A wide range of ratios of MS to DM (2:1, 1:1, and 1:2) were effective for preventing the development of morphine tolerance and dependence. In addition, we provide evidence that under certain circumstances DM increases the acute antinociceptive effects of MS. All of these results indicate that oral treatment that combines DM with opiate analgesics may be a powerful approach for simultaneously preventing opiate tolerance and dependence and enhancing analgesia in humans.

The central nucleus of the amygdala contributes to the production of morphine antinociception in the rat tail-flick test.

Current models of endogenous pain control circuitry emphasize neural substrates within the brainstem and spinal cord. We have recently shown, however, that the central nucleus of the amygdala (Ce) contributes to morphine-induced suppression of formalin-induced nociceptive behaviors. In the four experiments reported here, we investigated the possibility that the Ce also contributes to morphine-induced suppression of simple, spinally mediated nociceptive reflexes. Bilateral N-methyl-D-aspartate (NMDA)-induced lesions of the rat Ce, but not bilateral lesions centered on either the basolateral or medial amygdaloid nucleus, abolished the antinociception produced by 2.5 mg/kg morphine sulfate in the noxious heat-evoked tail-flick test. Bilateral Ce lesions also abolished the antinociception produced by 2 or 4 mg/kg morphine sulfate, but a relatively large dose of morphine sulfate (10 mg/kg, s.c.) resulted in partial reinstatement of antinociception. It is unlikely that these effects were due to secondary, seizure-induced damage following NMDA injection (e.g., to areas outside the amygdala) since bilateral inactivation of the Ce with the local anesthetic lidocaine also reliably attenuated morphine antinociception. It is also unlikely that these effects were artifacts of lesion-induced hyperalgesia, since Ce lesions failed to result in reliable thermal hyperalgesia, even at baseline tail-flick latencies of 10-12 sec. These data are the first to provide direct evidence that systemically administered morphine requires the integrity of a forebrain area in order to suppress spinally mediated nociceptive reflexes. It is argued that the present results, together with recent evidence linking the Ce to the production of several forms of conditioned and unconditioned environmentally induced antinociception, warrant incorporation of the Ce into current models of endogenous pain control circuitry.

Increases in protein kinase C gamma immunoreactivity in the spinal cord dorsal horn of rats with painful mononeuropathy.

Eight days after chronic constrictive sciatic nerve injury (CCI), protein kinase C gamma (PKC gamma) immunoreactivity reliably increased in the spinal cord dorsal horn of CCI rats with demonstrable thermal hyperalgesia as compared to sham-operated controls. Such PKC gamma immunostaining was observed primarily in neuronal somata (ipsilateral > contralateral, laminae I-II > III-IV), indicating postsynaptic sites of PKC gamma increases. Both the development of thermal hyperalgesia and the increase in PKC gamma immunoreactivity in CCI rats were prevented by once daily intrathecal administration with 10 nmol MK-801 for 7 days. The present results provide further evidence for a role of PKC in N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms of thermal hyperalgesia.

Increases in protein kinase C gamma immunoreactivity in the spinal cord of rats associated with tolerance to the analgesic effects of morphine.

Our previous studies have indicated a critical role of protein kinase C (PKC) in intracellular mechanisms of tolerance to morphine analgesia. In the present experiments, we examined (1) the cellular distribution of a PKC isoform (PKC gamma) in the spinal cord dorsal horn of rats associated with morphine tolerance by utilizing an immunocytochemical method and (2) the effects of the N-methyl-D-aspartate receptor antagonist MK-801 on tolerance-associated PKC gamma changes. In association with the development of tolerance to morphine analgesia induced by once daily intrathecal administration of 10 micrograms morphine for eight days, PKC gamma immunoreactivity was clearly increased in the spinal cord dorsal horn of these same rats. Within the spinal cord dorsal horn of morphine tolerant rats, there were significantly more PKC gamma immunostained neurons in laminae I-II than in laminae III-IV and V-VI. Such PKC gamma immunostaining was observed primarily in neuronal somata indicating a postsynaptic site of PKC gamma increases. Moreover, both the development of morphine tolerance and the increase in PKC gamma immunoreactivity were prevented by co-administration of morphine with 10 nmol MK-801 between Day 2 and Day 7 of the eight day treatment schedule. In contrast, PKC gamma immunoreactivity was not increased in rats receiving a single i.t. administration of 10 micrograms morphine on Day 8, nor did repeated treatment with 10 nmol MK-801 alone change baseline levels of PKC gamma immunoreactivity. These results provide further evidence for the involvement of PKC in NMDA receptor-mediated mechanisms of morphine tolerance.

The association of neuropathic pain, morphine tolerance and dependence, and the translocation of protein kinase C.

This series of studies has investigated the involvement of the NMDA receptor and the translocation of PKC in the seemingly unrelated phenomena of neuropathic pain and tolerance and dependence to narcotic analgesic drugs. This work has demonstrated that the NMDA receptor and PKC translocation are importantly involved in neuropathic pain and morphine tolerance or dependence and that these phenomena may be importantly interrelated. Neuropathic pain following nerve injury is a major chronic pain syndrome. Utilizing a rat model of painful peripheral mononeuropathy produced by CCI of the sciatic nerve, the authors have investigated central mechanisms of postinjury neuropathic pain. Behavioral and pharmacological studies indicate that thermal hyperalgesia and spontaneous pain behaviors observed in this model are attenuated by treatment with NMDA receptor antagonists. A consequence of NMDA receptor activation is calcium influx, which in turn can result in translocation of PKC from cytosol to membrane. Inhibitors of intracellular PKC translocation and activation block thermal hyperalgesia and spontaneous pain behaviors after CCI and also reduce the elevated spinal cord neural activity in CCI rats. Furthermore, spinal cord levels of membrane-bound PKC reliably increase in CCI rats as a result of translocation of PKC revealed by the [3H]PDBu autoradiographic assay. This increase in membrane-bound PKC is associated with postinjury neuropathic pain behaviors in CCI rats and both pain-related behaviors and membrane-bound PKC are reduced potently by GM1 ganglioside.

Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C.

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)

Spatial patterns of increased spinal cord membrane-bound protein kinase C and their relation to increases in 14C-2-deoxyglucose metabolic activity in rats with painful peripheral mononeuropathy.

1. Three-dimensional spatial patterns of changes in membrane-bound protein kinase C (PKC) were examined in the lumbar spinal cords (L1-L5) of rats with an experimental painful peripheral mononeuropathy. Painful peripheral mononeuropathy was produced by loosely ligating the rat's common sciatic nerve, resulting in chronic constrictive nerve injury (CCI). Changes in spinal cord membrane-bound PKC distribution were assayed by employing an established quantitative [3H]-phorbol-12,13-dibutyrate ([3H]PDBu) autoradiographic assay, which includes spinal cord sectioning, incubation of spinal cord sections with [3H]PDBu, production of autoradiographs, and computer-assisted image processing. 2. Sciatic nerve ligation induced demonstrable thermal hyperalgesia in response to radiant heat stimulation and spontaneous pain-related behaviors (such as lifting of the nerve-ligated hind paw) in CCI rats 3, 7, and 10 days after unilateral sciatic nerve ligation. 3. Consistent with behavioral changes, CCI rats examined 3 or 10 days after sciatic nerve ligation displayed a three-dimensional pattern of increased membrane-bound PKC in the lumbar spinal cord (L1-L5) strikingly different from that of sham-operated rats: in the dorsoventral dimension, reliable increases in membrane-bound PKC occurred mainly within spinal cord laminae I-IV and V-VI in CCI rats; in the ipsilateral-contralateral dimension, changes in membrane-bound PKC were seen on both sides of the spinal cord in CCI rats with reliably higher levels of membrane-bound PKC on the side ipsilateral than on the side contralateral to sciatic nerve ligation; in the rostrocaudal dimension, increases in membrane-bound PKC in the spinal cord dorsal horns of CCI rats extended from spinal segments L2-L5. 4. Both three-dimensional increases in spinal cord membrane-bound PKC and nociceptive behaviors (thermal hyperalgesia and spontaneous pain behaviors) in CCI rats were reliably reduced after three daily intrathecal treatments with 80 nmol GM1 ganglioside (a glycosphingolipid shown to prevent PKC translocation/activation), the first of which was given 1 h after sciatic nerve ligation. This reduction was seen 24 h but not 7 days after the last GM1 ganglioside treatment. 5. This three-dimensional increase in membrane-bound PKC in the spinal cord dorsal horn of CCI rats displayed high correlations with thermal hyperalgesia and with spontaneous pain-related behaviors in CCI rats observed both 3 and 10 days after sciatic nerve ligation. Similar correlations were observed between decreases in levels of membrane-bound PKC in the spinal cord dorsal horn and the attenuation of nociceptive behaviors in CCI rats after three daily intrathecal treatments with GM1 ganglioside.(ABSTRACT TRUNCATED AT 400 WORDS)

Patterns of increased brain activity indicative of pain in a rat model of peripheral mononeuropathy.

Regional changes in brain neural activity were examined in rats with painful peripheral mononeuropathy (chronic constrictive injury, CCI) by using the fully quantitative 14C-2-deoxyglucose (2-DG) autoradiographic technique to measure local glucose utilization rate. CCI rats used in the experiment exhibited demonstrable thermal hyperalgesia and spontaneous pain behaviors 10 d after sciatic nerve ligation when the 2-DG experiment was carried out. In the absence of overt peripheral stimulation, reliable increases in 2-DG metabolic activity were observed in CCI rats as compared to sham-operated rats within extensive brain regions that have been implicated in supraspinal nociceptive processing. These brain regions included cortical somatosensory areas, cingulate cortex, amygdala, ventral posterolateral thalamic nucleus, posterior thalamic nucleus, hypothalamic arcuate nucleus, central gray matter, deep layers of superior colliculus, pontine reticular nuclei, locus coeruleus, parabrachial nucleus, gigantocellular reticular nucleus, and paragigantocellular nucleus. The increase in 2-DG metabolic activity was bilateral in most brain regions of CCI rats. However, somatosensory regions within the thalamus and the cerebral cortex were activated in CCI rats. High levels of 2-DG metabolic activity were observed within the cortical hind limb area, ventral posterolateral thalamic nucleus, and posterior thalamic nucleus contralateral to the ligated sciatic nerve, and these levels were higher than ipsilateral corresponding regions in CCI rats. In addition, patterns of increased neural activity found in the brain of CCI rats showed some similarities and differences to those found in the brain of rats exposed to acute nociception induced by noxious heat or formalin stimulation. Thus, these CCI-induced spontaneous increases in neural activity within extensive brain regions of CCI rats previously implicated in sensory-discriminative and affective-motivational dimensions of pain as well as centrifugal modulation of pain are likely to reflect brain neural processing of spontaneous pain. Implications of increased brain neural activity in mechanisms of neuropathic pain are discussed with emphasis on correlations between spatial patterns of altered brain neural activity and pain-related behaviors in CCI rats and clinical symptoms in neuropathic pain patients.

Wide dynamic range but not nociceptive-specific neurons encode multidimensional features of prolonged repetitive heat pain.

1. To better characterize temporal and spatial mechanisms involved in the coding of prolonged nociceptive stimuli in the spinal cord, the responses of dorsal horn wide dynamic range (WDR) and nociceptive-specific (NS) neurons to prolonged, repetitive noxious heat stimuli (45-49 degrees C) were examined in unanesthetized, spinal cord transected rats. To relate these neuronal responses to conscious dimensions of pain, human subjects were presented with identical types of prolonged, repetitive stimuli, so that psychophysical ratings of pain intensity and pain unpleasantness could be compared with the magnitudes and temporal features of the responses of NS and WDR neurons. 2. WDR neurons exhibited high rates of impulse discharge throughout 45 min of repetitive nociceptive stimulation, with only partial reduction (31% decrease from peak rates) occurring after 2 min of stimulation. In sharp contrast, NS neurons stimulated under the same conditions displayed substantial reduction of firing (73% decrease from peak rates) after a brief, initial period of activity that occurred within 2 min after onset of stimulation. Psychophysical ratings of pain intensity and pain unpleasantness, like the responses of WDR neurons, did not decrease substantially from initial levels during 7 min of painful stimulation. Furthermore, these ratings remained at high levels during time periods where the impulse frequencies of NS neurons were only at 27% of maximal levels. 3. Graded nociceptive stimuli were employed to characterize the ability of WDR neurons to encode nociceptive intensity over long durations of repetitive stimulation and to delineate further the relationship between WDR and psychophysical responses. Both WDR discharge frequencies and psychophysical ratings of pain intensity and unpleasantness increased in a monotonic manner to graded increases in stimulus temperatures. 4. These results indicate that pain does not decrease substantially during the course of prolonged, repetitive nociceptive stimulation. The fact that the responses of NS neurons decline significantly, whereas both WDR and psychophysical responses do not, suggests that WDR neurons alone are sufficient to evoke both sensory intensity and affective responses to prolonged pain. Furthermore, because subjects could localize and qualitatively describe pain at times when responses of NS neurons were minimal, WDR neurons alone can encode some spatial and qualitative aspects of pain.

Intrathecal treatment with dextrorphan or ketamine potently reduces pain-related behaviors in a rat model of peripheral mononeuropathy.

The therapeutic effects of dextrorphan and ketamine, two non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, on neuropathic pain-related behaviors were examined in rats with peripheral mononeuropathy induced by loose ligation of the common sciatic nerve (chronic constrictive injury, CCI). Four daily intrathecal treatments (beginning 1 h after nerve ligation) with dextrorphan or ketamine (12.5-100 nmol) reliably attenuated hyperalgesia to radiant heat and spontaneous pain-related behaviors in CCI rats. Thermal hyperalgesia also was reduced in CCI rats receiving a single intrathecal treatment with either dextrorphan or ketamine (50 and 100 nmol for each compound) on day 3 after nerve ligation when thermal hyperalgesia was well developed. Since both dextrorphan and ketamine are currently utilized in other clinical applications, the results suggest a new therapeutic utility of these 'old' compounds in treatment of neuropathic pain syndromes resulting from peripheral nerve injury.

Differential roles of NMDA and non-NMDA receptor activation in induction and maintenance of thermal hyperalgesia in rats with painful peripheral mononeuropathy.

Central activation of excitatory amino acid receptors has been implicated in neuropathic pain following nerve injury. In a rat model of painful peripheral mononeuropathy, we compared the effects of non-competitive NMDA receptor antagonists (MK 801 and HA966) and a non-NMDA receptor antagonist (CNQX) on induction and maintenance of thermal hyperalgesia induced by chronic constrictive injury (CCI) of the rat common sciatic nerve. Thermal hyperalgesia to radiant heat was assessed by using a foot-withdrawal test and NMDA/non-NMDA receptor antagonists were administered intrathecally onto the lumbar spinal cord before and after nerve injury. Four daily single treatments with 20 nmol HA966 or CNQX beginning 15 min prior to nerve ligation (pre-injury treatment), reliably reduced thermal hyperalgesia in CCI rats on days 3, 5, 7 and 10 after nerve ligation. Thermal hyperalgesia was also reduced in CCI rats receiving a single post-injury treatment with HA966 (20 or 80 nmol) or MK 801 (5 or 20 nmol) on day 3 after nerve ligation when thermal hyperalgesia was well developed. In contrast, a single post-injury CNQX (20 or 80 nmol) treatment failed to reduce thermal hyperalgesia or to potentiate effects of HA966 or MK 801 (5 or 20 nmol) on thermal hyperalgesia in CCI rats. Moreover, multiple post-injury CNQX treatments utilizing the same dose regime as employed for the pre-injury treatment attenuated thermal hyperalgesia but only when the treatment began 1 or 24 h (but not 72 h) after nerve ligation.(ABSTRACT TRUNCATED AT 250 WORDS)