What makes mentors thrive? An exploratory study of their satisfaction in undergraduate medical education.

BACKGROUND: Mentoring medical students with varied backgrounds and individual needs can be challenging. Mentors' satisfaction is likely to be important for the quality and sustainability of mentorships, especially in programs where the mentor has responsibility for facilitating a group of mentees. However, little is known about what influences mentors' satisfaction. The aim of this study was to measure mentors' self-reported satisfaction with the mentoring experience and to explore associations between satisfaction and its putative factors. METHODS: An online survey was sent out to all physician mentors in each of the three mentorship programs (UiT The Arctic University of Norway, the University of Bergen, and McGill University, graduation years 2013-2020, n = 461). Data were analyzed by descriptive statistics, dimension reduction, and linear regression. RESULTS: On a scale from 1 to 5, mean mentor satisfaction score at two Norwegian and one Canadian medical school was 4.55 (95% CI 4.47, 4.64). In a multilevel multivariate regression analysis, two predictors were significantly associated with mentors' satisfaction: (1) the perception that students found the group meetings valuable (ß = 0.186, 95% CI 0.021, 0.351, p = 0.027) and (2) mentors' perceived rewards (ß = 0.330, 95% CI 0.224, 0.437, p < 0.001). Perceived rewards included experiencing gratifying relationships with students, and mentors' perception of self-development. CONCLUSIONS: In this study, mentors appeared to be highly satisfied with their mentoring functions. Our findings suggest that mentors' overall satisfaction is closely linked to their experiences of fulfilling mentor-student relationships and personal and professional development. Interestingly, and perhaps contrary to commonly held assumptions, we found no association between mentor satisfaction and financial compensation. Furthermore, satisfaction was not associated with the provision of pre-assigned topics for discussions for mentor group meetings. We propose that the mentors' experienced psycho-social rewards, and their competence in establishing well-functioning group dynamics, should be areas of focus for faculty development.

Endogenous descending modulation: spatiotemporal effect of dynamic imbalance between descending facilitation and inhibition of nociception.

In conscious rats, we investigated the change of nociceptive paw withdrawal reflexes elicited by mechanical and heat stimuli during intramuscular (i.m.) 5.8% hypertonic (HT) saline elicited muscle nociception. i.m. injection of HT saline caused rapid onset, long lasting (around 7 days), bilateral mechanical hyperalgesia, while it induced bilateral, slower onset (1 day after the HT saline injection), long-term (about 1-2 weeks) heat hypoalgesia. Ipsilateral topical pre-treatment of the sciatic nerve with 1% capsaicin significantly prevented the occurrence of both the bilateral mechanical hyperalgesia and the contralateral heat hypoalgesia. Intrathecal administration of either 6-hydroxydopamine hydrobromide (6-OHDA) or 5,7-dihydroxytryptamine (5,7-DHT), and intraperitoneal injection of naloxone all markedly attenuated the HT saline induced bilateral heat hypoalgesia, but not the mechanical hyperalgesia. Combined with experiments with lesioning of the rostroventral medulla with kainic acid, the present data indicate that unilateral i.m. injection of HT saline elicits time-dependent bilateral long-term mechanical hyperalgesia and heat hypoalgesia, which were modulated by descending facilitatory and inhibitory controls, respectively. We hypothesize that supraspinal structures may function to discriminate between afferent noxious inputs mediated by Aδ- and C-fibres, either facilitating Aδ-fibre mediated responses or inhibiting C-fibre mediated activities. However, this discriminative function is physiologically silent or inactive, and can be triggered by stimulation of peripheral C-fibre afferents. Importantly, in contrast to the rapid onset of descending facilitation, the late occurrence of descending inhibition suggests a requirement of continuous C-fibre input and temporal summation. Thus, a reduction of C-fibre input using exogenous analgesic agents, i.e. opioids, may counteract the endogenous descending inhibition.

High-frequency conditioning electrical stimulation evokes supraspinal independent long-term depression but not long-term potentiation of the spinal withdrawal reflex in rats.

The aim of the current study was to investigate the effects on the spinal withdrawal reflex of electrical stimulation that has been shown to induce long-term potentiation (LTP) in spinal sensory systems. This was done in order to enhance our understanding of long-term dynamic modifications of spinal motor system during the exposure to high-frequency conditioning electrical stimulation (cES). The spinal withdrawal reflex was assessed by extracellular recording of the single motor unit (SMU) electromyographic (EMG) activity from the medial gastrocnemius (MG) muscle in intact and acutely spinalized rats. High-frequency (1 ms pulses at 100 Hz for 2 s repeated three times at 10 s intervals) tetanic cES produced a significant long-term depression (LTD) (at least 3 h), but not LTP, of the electrically evoked SMU EMG activity as well as the wind-up phenomenon (temporal summation). There were no significant depressive or facilitatory effects of low-frequency (2 Hz) cES, consisting of the same number of pulses as the 100 Hz cES, on the SMU EMG responses. This frequency-dependent long-term depressive effect on the spinal withdrawal reflex was not significantly changed following acute spinalization, indicating that LTD of the spinal motor system elicited by high-frequency cES is independent of the descending control system. We conclude that, in contrast to LTP in spinal sensory systems to brief tetanic C-fiber cES, high-frequency cES seems only to elicit LTD of motor systems of the spinal cord.

Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy.

BACKGROUND AND AIMS: Peripheral neuropathic pain is described as a pain state caused by an injury or dysfunction of the nervous system, and could have clinical manifestations such as hyperalgesia, allodynia and spontaneous pain. The development of neuropathic pain may depend on long-term forms of neuronal plasticity in the spinal cord (SC). Expression of the immediate early gene proteins (IEGPs) Arc, Zif268, and c-Fos are implicated in establishment of long-term potentiation (LTP) induced by conditioning stimulation (CS) of primary afferent fibres. However, the impact of the neuropathic state (Bennett's model) on CS-induced expression of IEGPs has not been studied. The aim of this study was to compare the levels of Arc, c-Fos and Zif268 immunoreactivity prior to and after conditioning stimulation in animals with developed neuropathic pain, with sham operated, non-ligated controls. METHODS: Twenty-four animals were divided equally into the neuropathic and non-neuropathic groups. Neuropathic pain was induced in all animals by conducting a loose ligation of the sciatic nerve with Chromic Catgut 4.0 sutures 7 days prior to conditioning stimulation or sham operation. The loose ligation was performed by placing sutures around the sciatic nerve compressing the nerve slightly just enough to reduce but not completely diminish the perineural circulation. A state of neuropathy was confirmed by a significant decrease in mechanical withdrawal threshold measured by von Frey's fibres. Immunohistochemical analysis was performed on transverse sections obtained from the L3-L5 segments of the SC at 2 and 6h post-CS and IEGP positive cells were counted in lamina I and II of the dorsal horn. During statistical analyses, the groups were compared by means of analysis of variance (univariate general linear model). If significant differences were found, each set of animals was compared with the sham group with post hoc Tukey's multiple comparison test. RESULTS: Strikingly, all IEGPs exhibited a significant increase in immunoreactivity at both time points compared to time-matched, sham operated controls. Maximal IEGP expression was found 2h after CS in neuropathic rats, and there was a smaller but still significant increase 6h after CS. The unstimulated side of the dorsal horn in stimulated animals did not show any significant change of the number of IEGP positive cells and was approximately at the same level as sham operated animals. The number of IEGP positive cells in sham operated controls (non-neuropathic and non-stimulated animals) showed same immunoreactivity in 2 and 6h post sham operation. CONCLUSIONS AND IMPLICATIONS: The neurophysiological process of neuropathic pain development is complex and needs to be studied further in order to clarify its nature and components. This present study is meant to reveal a step towards further understanding the role of Arc, c-Fos and Zif268 in neuropathic pain. Moreover, this study might contribute to the knowledge base for further research on better therapeutic possibilities for neuropathic pain.

Long-term potentiation in spinal nociceptive systems--how acute pain may become chronic.

Chronic pain is a major problem since it is difficult to treat and the understanding of the underlying neurobiology is sparse. The mechanisms underpinning the transition of acute into chronic pain remain unclear. However, long-term potentiation (LTP) in spinal nociceptive systems may be one such mechanism. Here, we briefly review the literature regarding LTP in spinal nociceptive systems including our own data on LTP in deep convergent nociceptive neurons. Furthermore, we discuss the role of this phenomenon in understanding the neurobiology of chronic pain and the possible therapeutic implications.

[Molecular mechanisms in acute and chronic pain states]. / Molekylaere mekanismer ved akutte og kroniske smerter.

BACKGROUND: Pain is a sense necessary for survival and has a complex neurobiological basis. In recent years a powerful battery of techniques has been developed to unravel the mechanisms by which painful stimuli are transduced and processed both in the acute and pathological state. MATERIAL AND ANALYSIS: We review the literature with special emphasis on recent discoveries regarding the molecular transduction mechanisms in nociceptors and novel molecular and cellular mechanisms underlying the spinal processing of painful stimuli. RESULTS AND INTERPRETATION: The mechanisms by which sensory neurons initiate hyperalgesia and touch-evoked pain (allodynia) have been addressed particularly successfully in recent studies. The rich variety of key molecular players that have emerged in physiological and pathophysiological pain states reflects the sophistication and uniqueness of this important sense. This is good news for both the pain scientist and the pain clinician since it increases the intellectual challenge and provides a plethora of targets for novel analgesics and treatments.

Chronic morphine treatment enhances sciatic nerve stimulation-induced immediate early gene expression in the rat dorsal horn.

Synaptic plasticity is a property of neurons that can be induced by conditioning electrical stimulation (CS) of afferent fibers in the spinal cord. This is a widely studied property of spinal cord and hippocampal neurons. CS has been shown to trigger enhanced expression of immediate early gene proteins (IEGPs), with peak increases observed 2 hour post stimulation. Chronic morphine treatment has been shown to promoteinduce opioid-induced hyperalgesia, and also to increase CS-induced central sensitization in the dorsal horn. As IEGP expression may contribute to development of chronic pain states, we aimed to determine whether chronic morphine treatment affects the expression of IEGPs following sciatic nerve CS. Changes in expression of the IEGPs Arc, c-Fos or Zif268 were determined in cells of the lumbar dorsal horn of the spinal cord. Chronic Morphine pretreatment over 7 days led to a significant increase in the number of IEGP positive cells observed at both 2 h and 6 h after CS. The same pattern of immunoreactivity was obtained for all IEGPs, with peak increases occurring at 2 h post CS. In contrast, morphine treatment alone in sham operated animals had no effect on IEGP expression. We conclude that chronic morphine treatment enhances stimulus-induced expression of IEGPs in the lumbar dorsal horn. These data support the notion that morphine alters gene expression responses linked to nociceptive stimulation and plasticity.

Time course of immediate early gene protein expression in the spinal cord following conditioning stimulation of the sciatic nerve in rats.

Long-term potentiation induced by conditioning electrical stimulation of afferent fibers is a widely studied form of synaptic plasticity in the brain and the spinal cord. In the spinal cord dorsal horn, long-term potentiation is induced by a series of high-frequency trains applied to primary afferent fibers. Conditioning stimulation (CS) of sciatic nerve primary afferent fibers also induces expression of immediate early gene proteins in the lumbar spinal cord. However, the time course of immediate early gene expression and the rostral-caudal distribution of expression in the spinal cord have not been systematically studied. Here, we examined the effects of sciatic nerve conditioning stimulation (10 stimulus trains, 0.5 ms stimuli, 7.2 mA, 100 Hz, train duration 2 s, 8 s intervals between trains) on cellular expression of immediate early genes, Arc, c-Fos and Zif268, in anesthetized rats. Immunohistochemical analysis was performed on sagittal sections obtained from Th13- L5 segments of the spinal cord at 1, 2, 3, 6 and 12 h post-CS. Strikingly, all immediate early genes exhibited a monophasic increase in expression with peak increases detected in dorsal horn neurons at 2 hours post-CS. Regional analysis showed peak increases at the location between the L3 and L4 spinal segments. Both Arc, c-Fos and Zif268 remained significantly elevated at 2 hours, followed by a sharp decrease in immediate early gene expression between 2 and 3 hours post-CS. Colocalization analysis performed at 2 hours post-CS showed that all c-Fos and Zif268 neurons were positive for Arc, while 30% and 43% of Arc positive neurons were positive for c-Fos and Zif268, respectively. The present study identifies the spinal cord level and time course of immediate early gene (IEGP) expression of relevance for analysis of IEGPs function in neuronal plasticity and nociception.

The tail-flick and formalin tests in rodents: changes in skin temperature as a confounding factor.

In the tail-flick test as well as in the late phase in the formalin test skin temperature may in an important way influence the response. A reduced skin temperature may be misinterpreted as analgesia, and an increased skin temperature as hyperalgesia. These effects and the mechanisms that cause them are discussed. It is of particular importance to be aware of these confounding factors when using drugs or making lesions that influence blood flow or temperature regulation. It is important that all variables influencing the test results are kept constant throughout the experiment. This includes not only the ambient temperature, but also factors that may influence the vasomotor tone of the animals.

The apparent antinociceptive effect of desipramine and zimelidine in the tail flick test in rats is mainly caused by changes in tail skin temperature.

Tricyclic antidepressants have shown antinociceptive properties in some, but not in all, animal studies using the tail flick test. Tail flick latency has been found to be strongly negatively correlated to tail skin temperature with its highest correlation found when the temperature is measured close to the heated spot. The selective 5-HT reuptake inhibitor zimelidine, as well as the noradrenaline reuptake inhibitor desipramine, increased tail flick latencies. However, this increase could largely be explained by a concomitant reduction in tail skin temperature. The highest dose of desipramine investigated (25 mg/kg) seemed to possess antinociceptive properties in this test also after correction for the fall in tail skin temperature. Lower doses of desipramine (5 and 15 mg/kg) and zimelidine (5, 20 and 30 mg/kg) were either inactive or their effect on tail flick latency could be explained by the fall in tail skin temperature. The apparent antinociceptive effect of zimelidine in the tail flick test thus seems to be due to an effect on tail skin temperature. Desipramine also seems to have its main effect due to a similar mechanism; however, the highest dose of desipramine used induced significant antinociception.

The role of descending noradrenergic systems in regulation of nociception: the effects of intrathecally administered alpha-adrenoceptor antagonists and clonidine.

It has been proposed that descending noradrenergic systems exercise a tonic inhibition of nociception at the spinal level. The recent finding that changes in tail skin temperature (TT) may have a strong effect on the tail-flick latency makes a reevaluation of this hypothesis necessary. The alpha-adrenoceptor agonist clonidine injected intrathecally (i.th.) in a dose of 60 micrograms increased the response temperature in the increasing hot plate test 10 min after injection, and prolonged the tail-flick latency 30-60 min after injection. A considerable part of the change in tail-flick latency was caused by a reduction in TT. The alpha 1-antagonist prazosin (30 and 60 micrograms) tended to increase the response temperature in the increasing hot plate test after 60 min, and to prolong the latency in the tail-flick test. These effects were not statistically significant. Clonidine and prazosin induced sensorimotor impairment and a reduction in body temperature after 30-60 min. The alpha 2-antagonist yohimbine had no effect in the increasing hot plate test, but reduced the tail-flick latency 10 min after drug administration. This reduction could be explained by an increase in TT. The results suggest that the reduced latency in the tail-flick test after i.th. injection of yohimbine is caused by an increase in the tail blood flow, and does not support the hypothesis of a tonic bulbospinal noradrenergic inhibition of nociception. The time course of response latencies suggests that supraspinal mechanisms may be involved in the effects of i.th. clonidine and prazosin in the tail-flick test, while there seems to be a spinally mediated antinociceptive effect of clonidine that can be demonstrated in the increasing hot plate test.

Induction of long-term potentiation of single wide dynamic range neurones in the dorsal horn is inhibited by descending pathways.

Previous studies have shown that long-term potentiation (LTP) in the dorsal horn may be induced by noxious stimuli. In this study it is investigated whether induction of LTP in the dorsal horn may be affected by the descending pathways. Extracellular recordings of wide dynamic range (WDR) neurones in the lumbar dorsal horn in intact urethane-anaesthetized Sprague--Dawley rats were performed, and the electrically evoked neuronal responses in these neurones were defined as A-fibre and C-fibre responses according to latencies. Using a short-term cold block of the thoracic spinal cord, which produced a completely reversible increase of the A-fibre and C-fibre responses, the influence of the descending inhibitory system on the induction of LTP by electrical high-frequency conditioning applied to the sciatic nerve was examined. As previously shown the A-fibre responses were almost unchanged following the conditioning. In contrast, the C-fibre responses following the same conditioning were strongly increased. Thus, a clear LTP of the nociceptive transmission in the dorsal horn was observed following electrical high-frequency conditioning. Interestingly, we found that the LTP was more powerful when the effects of the descending pathways were temporarily eliminated during conditioning. It is concluded that induction of LTP by electrical high-frequency conditioning stimulation, which may be part of the wider term central sensitization, is inhibited by descending pathways.

The formalin test in mice: effect of formalin concentration.

The effect of different formalin concentrations on the nociceptive response in the formalin test was examined in mice. Subcutaneous formalin injection induces 2 distinct periods of high licking activity: an early phase lasting the first 5 min, and a late phase lasting 20-30 min after the injection. Formalin concentrations of 0.02-0.2% induced only the early phase, while concentrations of 1% or more induced both the early phase and the late phase. The ability of the test to show the antinociceptive effect of morphine and acetylsalicylic acid was similar for high and low formalin concentrations. For both these analgesics, a lower dose was needed to induce antinociception in the late phase than in the early phase using the same formalin concentration. Indomethacin had no effect in the early phase. In the late phase indomethacin induced antinociception when 1% formalin was used, while no significant effect was observed using 5% formalin. Clear histological changes in the paw were demonstrated after formalin concentrations that induced both phases. Lower formalin concentrations induced only very small changes. Using a low formalin concentration (0.2%), repeated testing using the same paw could be performed at intervals of 1 week without any significant change in the response. It was concluded that the formalin concentration should be kept as low as possible to minimize the suffering of the animal. Formalin concentrations of 0.05-0.2% are recommended for studying the early phase. Formalin concentrations of 1% or higher have to be used when studying the nociceptive response in the late phase.

Increased spinal N-methyl-D-aspartate receptor function after 20 h of carrageenan-induced inflammation.

Spinal N-methyl-D-aspartate (NMDA) receptors are thought to be important in states of central hyperexcitability induced by e.g. inflammation or painful neuropathies. The carrageenan model of inflammatory pain has been and still is widely used as is the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5) to investigate NMDA receptor function. Here we present two novel findings using electrophysiological technique: the NMDA receptor function in the spinal cord is increased following 20 h of carrageenan-induced inflammation and further that only the D-isomer of AP5 is active in the spinal cord. Exogenous NMDA (0.5 and 5 nmol) applied onto the dorsal spinal cord produced a significantly greater facilitation and D-AP5 (1.25 micromol) a significantly greater inhibition of the C-fibre evoked response of the wide dynamic range (WDR) neurones studied in carrageenan (20 h after injection) compared to control rats. The present and two recent studies suggest central changes are different and possibly greater in the later (20 h) compared to the earlier (2-6 h) phase of carrageenan-induced inflammation. In conclusion, 20 h of carrageenan-induced inflammation increases the function of spinal NMDA receptor involved in nociceptive transmission and in addition the D-isomer of AP5 should be used when NMDA receptor antagonism is wanted in the spinal cord.

Dorsal horn NMDA receptor function is changed after peripheral inflammation.

The N-methyl-D-aspartic acid (NMDA) receptor antagonist D, L-2-amino-5-phosphonopentanoic acid (AP5) caused a stronger inhibition of wind-up in single wide dynamic range (WDR) neurons after carrageenan inflammation compared with control neurons without inflammation in the receptive field. This indicates that even a short period (2.5 h) of inflammation induces changes in the function of NMDA receptors. The drug effect was also studied in separate control experiments with few wind-up inducing stimulus trains and little nociceptive input prior to baseline recordings. In these control experiments all evoked responses were reduced by the drug, but the wind-up was significantly increased. A wind-up increase after NMDA receptor antagonism has been reported in two previous studies. Thus, other mechanisms than NMDA receptor stimulation may be more important for the wind-up in not sensitized dorsal horn neurons. As for long-term potentiation, it seems that NMDA receptor antagonists have an increased effect after sensitization. Thus, sensitized and not sensitized dorsal horn neurons may respond differently to an NMDA receptor active drug. In rats nerve stimulation and halothane anaesthesia induced larger evoked responses to afferent stimulation than cutaneous stimulation and urethane anaesthesia, the AP5 effect was however similar.

Natural noxious stimulation can induce long-term increase of spinal nociceptive responses.

It is conceivable that plasticity in pain control systems and chronic pain may be due to mechanisms similar to learning. Long-term potentiation (LTP) in the hippocampus is often studied as a model of learning and memory. It has recently been shown that long-term excitation may be induced in single wide dynamic range (WDR) neurones in the spinal dorsal horn of rats after tetanic stimulation to the sciatic nerve. The present study shows that similar long-term changes can also be induced by a severe natural stimulus. Single unit extracellular recordings were made in urethane anaesthetized rats and the firing responses of WDR neurones evoked by a single electrical stimulus to the peripheral nerve were recorded every 4 min. After repeated crushing of tissue (including bone) corresponding to the receptive field of the WDR neurones (the conditioning stimulus) followed by a proximal total peripheral nerve block, the C-fibre evoked responses were increased (P < 0.001) for a 3 h observation period compared with baseline responses and control animals. In control animals the nerve block was applied before the conditioning stimulus. We suggest that a long-term increase of the excitability of WDR neurones may be important for the development of long lasting and chronic pain disorders after an acute but severe noxious stimulus.

Apparent hyperalgesia after lesions of the descending serotonergic pathways is due to increased tail skin temperature.

It has been suggested that the descending serotonergic pathways exercise a tonic inhibition on nociception in the spinal cord. In this study 5,6-dihydroxytryptamine (5,6-DHT, 20 micrograms base) injected intrathecally in rats reduced spinal serotonin concentration to 3.5% of control levels without significantly affecting spinal noradrenaline. The lesion reduced the mean tail-flick latency by approximately 35% and increased the mean tail skin temperature by approximately 3.5 degrees C; both parameters gradually returned to normal values within 2-3 weeks. Both in controls and in lesioned animals there was a highly significant negative correlation between tail skin temperature and tail-flick latency. Multiple regression analysis showed that the effect of lesioning on tail-flick latency was non-significant when the effect of skin temperature was taken into account. Thus the reduced tail-flick latency after lesions of descending serotonergic pathways, usually interpreted as increased nociception, may be due to changes in tail skin temperature.

The formalin test: an evaluation of the method.

The formalin test for nociception, which is predominantly used with rats and mice, involves moderate, continuous pain generated by injured tissue. In this way it differs from most traditional tests of nociception which rely upon brief stimuli of threshold intensity. In this article we describe the main features of the formalin test, including the characteristics of the stimulus and how changes in nociceptive behaviour may be measured and interpreted. The response to formalin shows an early and a late phase. The early phase seems to be caused predominantly by C-fibre activation due to the peripheral stimulus, while the late phase appears to be dependent on the combination of an inflammatory reaction in the peripheral tissue and functional changes in the dorsal horn of the spinal cord. These functional changes seem to be initiated by the C-fibre barrage during the early phase. In mice, the behavioural response in the late phase depends on the ambient temperature. We argue that the peripheral tissue temperature as well as other factors influencing the peripheral inflammation may affect the response, possibly confounding the results obtained with the test. Furthermore, we discuss the methods of recording the response and the value of observing more than one aspect of behaviour. Scoring of several behavioural variables provides a means of assessing motor or sensorimotor function as possible causes for changes in behaviour. In conclusion, the formalin test is a valuable addition to the battery of methods available to study nociception.

Spinal substance P release in vivo during the induction of long-term potentiation in dorsal horn neurons.

Long-term potentiation (LTP) in wide dynamic range (WDR) neurons in the dorsal horn has been suggested to contribute to central sensitization and the development of chronic pain. Indirect experimental evidence indicates an involvement of substance P (SP), in this respect. The aim of the present study was to monitor the extracellular level of substance P-like immunoreactivity (SP-LI) in the dorsal horn of the rat during and after induction of LTP in WDR neurons in vivo. Electrophysiological recordings of single (WDR) neurons were performed in parallel with microdialysis in the dorsal horn under urethane-anaesthesia. The amount of SP-LI in the microdialysate was determined by radioimmunoassay. As previously shown, high frequency conditioning stimulation of the sciatic nerve induced an increased firing response of WDR neurons. An increased response to C-fibre stimulation, but not A-fibre stimulation, could be determined. A significant increase of the extracellular level of SP-LI in the dorsal horn was detected during, but not after, induction of LTP. These data suggest that SP may be involved in the induction of LTP by high frequency stimulation. However, the maintenance of spinal LTP following high frequency peripheral nerve stimulation does not seem to depend on an increased release of SP.

Exaggerated nociceptive responses on morphine withdrawal: roles of protein kinase C epsilon and gamma.

On withdrawal from opioids many patients experience a heightened sensitivity to stimuli and an exaggerated pain response. The phenomenon has been little studied in infants. We present evidence that in postnatal day 7 rats an exaggerated nociceptive ventral root response of spinal cords in vitro and withdrawal-associated thermal hyperalgesia in vivo are dependent on protein kinase C (PKC), and we document the roles of PKC and gamma isozymes. In vitro, the slow ventral root potential (sVRP) is a nociceptive-related response in spinal cord that is depressed by morphine and recovers to levels significantly above control on administration of naloxone. A broad-spectrum PKC antagonist, GF109213X, blocked withdrawal hyperresponsiveness of the sVRP whereas an antagonist specific to Ca(++)-dependent isozymes, Go69076, did not. Consistent with this finding, a specific peptide inhibitor of calcium-independent PKC, but not an inhibitor of calcium-dependent PKC gamma, blocked withdrawal hyperresponsiveness of the sVRP. Similarly, in vivo in 7-day-old rat pups, inhibition of PKC, but not PKC gamma, prevented thermal hyperalgesia precipitated by naloxone at 30 min post-morphine. In contrast, thermal hyperalgesia during spontaneous withdrawal was inhibited by both PKC and gamma inhibitors. The consistency between the in vivo and in vitro findings with respect to naloxone-precipitated withdrawal provides further evidence that the sVRP reflects nociceptive neurotransmission. In addition the difference between naloxone-precipitated and spontaneous withdrawal in vivo suggests that in postnatal day 7 rats, morphine exposure produces an early phase of primary afferent sensitization dependent upon PKC translocation, followed by a later phase involving spinal sensitization mediated by PKC gamma.