Gideon Urca

Characterization of chronic pain and somatosensory function in spinal cord injury subjects.

&NA; The pathophysiology of the chronic pain following spinal cord injury (SCI) is unclear. In order to study its underlying mechanism we characterized the neurological profile of SCI subjects with (SCIP) and without (SCINP) chronic pain. Characterization comprised of thermal threshold testing for warmth, cold and heat pain and tactile sensibility testing of touch, graphesthesia and identification of speed of movement of touch stimuli on the skin. In addition, spontaneously painful areas were mapped in SCIP and evoked pathological pain – allodynia, hyperpathia and wind‐up pain evaluated for both groups. Both SCIP and SCINP showed similar reductions in both thermal and tactile sensations. In both groups thermal sensations were significantly more impaired than tactile sensations. Chronic pain was present only in skin areas below the lesion with impaired or absent temperature and heat‐pain sensibilities. Conversely, all the thermally impaired skin areas in SCIP were painful while painfree areas in the same subjects were normal. In contrast, chronic pain could be found in skin areas without any impairment in tactile sensibilities. Allodynia could only be elicited in SCIP and a significantly higher incidence of pathologically evoked pain (i.e. hyperpathia and wind‐up pain) was seen in the chronic pain areas compared to SCINP. We conclude that damage to the spinothalamic tract (STT) is a necessary condition for the occurrence of chronic pain following SCI. However, STT lesion is not a sufficient condition since it could also be found in SCINP. The abnormal evoked pain seen in SCIP is probably due to neuronal hyperexcitability in these subjects. The fact that apparently identical sensory impairments manifest as chronic pain and hyperexcitability in one subject but not in another implies that either genetic predisposition or subtle differences in the nature of spinal injury determine the emergence of chronic pain following SCI.

IntrathecalN-methyl-d-aspartate (NMDA) activates both nociceptive and antinociceptive systems

Injection of the excitatory amino acid N-methyl-D-aspartate (NMDA) into the spinal subarachnoid space of rats produces both hyperalgesic and analgesic effects. At lower concentrations (0.5 mM) little behavioral effect is elicited by the drug. However, brief hyperalgesia followed by several minutes of analgesia can be detected in these animals. Higher concentrations of the drug produce vocalization, caudally directed scratching and biting and hyper-responsiveness to light touch. The NMDA antagonist, arginine vasopressin, produces analgesia when injected by itself and completely reverses all effects of NMDA. NMDA-induced analgesia, but not hyperalgesia, is reversed by intrathecal administration of naloxone, methysergide and phentolamine. The analgesic effects of both agonist and antagonist are markedly potentiated by spinalization. These results suggest the involvement of NMDA receptors in both the transmission of pain and the mediation of spinal segmental pain inhibitory mechanism.

Is substance P a primary afferent neurotransmitter for nociceptive input? I. Analysis of pain-related behaviors resulting from intrathecal administration of substance P and 6 excitatory compounds

Intrathecal (i.t.) injection of substance P (SP), capsaicin, kainic acid, picrotoxin, strychnine, morphine, and L-glutamic acid in rats induced rhythmic scratching movements with the hindlimbs, biting, and, with some of these compounds, vocalization and myoclonic twitches. Although biting was directed to the dermatome corresponding to the injection site, scratching was aimed at anterior dermatomes. Presumably painful chemical stimulation produced by cutaneous and subcutaneous application of capsaicin or acetic acid never elicited scratching. Vocalization was never elicited by SP. When vocalization occurred following i.t. picrotoxin and morphine, it was correlated with myoclonic twitches rather than with scratching and/or biting. These findings indicate that scratching (a) is not pain-related and, (b) when elicited by the i.t. administration of the compounds listed above, does not result from activation of nociceptive primary afferent synapses.

Development of thermal nociception in rats

&NA; In the present study, we show that hypersensitivity to noxious thermal stimulation can be seen clearly in developing rats. Rats, at postnatal days 3, 6, 9, 12, 15, 21 and 90 were tested for reflex responsiveness to noxious heat, using tail withdrawal from hot water as the assay. Thermal nociceptive thresholds are considerably lowered, relative to adults, up to postnatal day 12. Thresholds were 39, 37.5, 40.8, 43.3, 46.5, 45.2 and 47.2°C for the respective age groups. Enhanced sensitivity to suprathreshold noxious stimuli is seen in neonates up to postnatal day 15 (but not on day 9). Starting on day 21, sensitivity to noxious stimuli decreases with increasing age, as can be seen by the decrease in the slope of the temperature‐response curve (system gain). Spinal transections at postnatal days 13, 17, 20, 60, or 100 did not produce a change in nociceptive thresholds in any of the age groups. In contrast, sensitivity to noxious stimulation (system gain) was enhanced by spinalization in rats 20 days of age or older. Based on these results we suggest that threshold elevation with increasing age most probably reflects changes in local spinal properties, while changes in responsiveness to suprathreshold noxious stimuli involves maturation of both spinal and descending supraspinal structures.

Analgesic and hyperalgesic effects of midazolam: dependence on route of administration

The effects of intraperitonenl (IP) and lumbar intrathecal (IT) midazolam (MID) on nociception was studied in 38 male albino rats using the noxious tale-flick and hot-plate tests. Four groups received IP 0.1, 1, and 10 mg/kg MID or an equal volume of its vehicle benzyl alcohol 0.1 mg in 1 ml saline, while the other three groups received IT 10 and 100 μg MID or 0.5 μg benzyl alcohol in 5 μl saline. The two higher doses of IP MID produced statistically significant decrease of tale-flick latencies (P < 0.005 and 0.05 at 10 and 100 mg/kg MID, respectively). This hyperalgesic effect could be seen, although the animals appeared highly sedated with reduced motor activity and relatively unresponsive to non-noxious stimuli. In contrast, IT injections of 10 μg MID produced moderate but statistically significant prolongation of tail-flick latencies (P < 0.05) without noticeable change in motor activity. This analgesic effect could not be observed with the higher dose of IT MID until an hour after its administration. The almost complete immobility and ataxia seen after the high doses of IP and IT MID (animals lying on their sides) precluded reliable hot plate testing in these animals. Apparently part of the high IT dose of MID diffused into the brain, as observed after high-dose IP administration. We therefore propose that the analgesic effect of midazolam stems from its action at the spinal level, while its sedative and hyperalgesic effects are a function of its supraspinal action.

Neurotoxic effects of excitatory amino acids in the mouse spinal cord: quisqualate and kainate but not N-methyl-l-aspartate induce permanent neural damage

Despite extensive evidence for the neurotoxic effects of excitatory amino acids (EAA) in the brain little is known about their neurotoxic action in the spinal cord. In this study we attempted to produce differential lesions of spinal neurons by pretreating mice, intrathecally, with high concentrations of the EAA: N-methyl-D-aspartate (NMDA), quisqualate and kainate. Pharmacological, behavioral and histological consequences were examined 1, 3, 7 and, in some cases, 30 days after pretreatment. A single, intrathecal, injection of high concentrations of quisqualate and kainate but not NMDA, resulted in damage to spinal cord neurons. The highest concentrations of these agonists produced, in some animals, a massive, non-selective destruction of neurons within the lumbar spinal cord, accompanied by complete paralysis of the hindlimbs. Pretreatment with lower concentrations of intrathecal kainate or quisqualate produced damage to spinal interneurons, as well as more limited damage to motor neurons. No detectable motor deficit could be detected but a decrease in responsiveness to noxious stimuli was observed. Such damage also manifest as a permanent decrease in the sensitivity of the spinal interneurons, as well as more limited damage to motor neurons. No detectable motor deficit could be detected but a decrease in responsiveness to noxious stimuli was observed. Such damage also manifest as a permanent decrease in the sensitivity of the spinal cord to EAA, as seen from the decrease in biting behavior elicited by intrathecal EAA. The neurotoxic effects of quisqualate were completely blocked by the quisqualate/kainate receptor antagonist glutamylaminomethylsulphonate (GAMS), but not the NMDA antagonist 2-amino-5-phosphovalerate. GAMS attenuated the effects of kainate only partially.(ABSTRACT TRUNCATED AT 250 WORDS)

Spatial summation of heat pain: a reassessment.

&NA; Heat pain threshold is commonly considered to be an ‘absolute’ value, which is not dependent on the area stimulated. In contrast, suprathreshold heat pain sensation has been shown to be highly dependent on the area stimulated, with considerable spatial summation demonstrated both within and between dermatomes. The present study sought to reevaluate two major issues: (a) Whether nociceptive thresholds are, indeed, independent of stimulation area. (b) Whether the spatial summation of suprathreshold heat pain sensation is independent of threshold changes. Using noxious heat we evaluated nociceptive thresholds and perceived pain intensity for contact areas of 0.25, 2.25, 6.25 and 15.36 cm2. Our results show that considerable spatial summation of heat pain thresholds is obtained and an apparent spatial summation of perceived intensity can also be observed. However, these apparent changes in perceived pain intensity can be accounted for completely by the changes in noxious heat thresholds. Furthermore, when using a stimulus configuration in which stimulation area was increased without changing nociceptive threshold, no spatial summation of perceived pain intensity was seen. Our results suggest that the spatial summation of perceived heat pain intensity can be attributed to reduced heat pain threshold. Furthermore, our findings stress the importance of determining pain thresholds in studies examining the psychophysics of suprathreshold noxious stimuli.

Different opioid systems may participate in post-electro-convulsive shock (ECS) analgesia and catalepsy

Administration of electroconvulsive shock (ECS) to rats results in post-ictal analgesia and catalepsy both of which can be partially reversed by the opiate antagonists, naloxone and naltrexone. Tolerance to both phenomena develops following daily ECS administration for 10 days. However, qualitatively different patterns of tolerance development of analgesia and catalepsy are seen. Naloxone treatment prior to ECS provides partial protection against the development of tolerance to ECS-induced catalepsy but does not present the tolerance to post-ECS analgesia. In contrast, the long-lasting opiate antagonist, naltrexone, blocked the development of tolerance to ECS analgesia. Furthermore, the same animals that showed tolerance to the analgesic effects of repeated ECS failed to show analgesia following the administration of 10 mg/kg of morphine while naltrexone, but not naloxone, treatment prior to ECS blocked the development of cross-tolerance to morphine analgesia. A dose-response investigation of morphines action (5, 10, 15 and 20 mg/kg) in additional animals receiving 10 daily administrations of ECS reveals that a greater tolerance to morphines motor inhibitory effect than to its analgesic effect results from repeated ECS administration. Finally, animals receiving daily injections of either a low (10 mg/kg) or a high (100 mg/kg) dose of morphine for 10 days showed markedly attenuated post-ECS analgesia and catalepsy. However, whereas similar effects of opiate antagonists and the chronic administration of both doses of morphine were observed with post-ECS catalepsy, analgesia was least affected by naloxone (50% of control) and most affected by the chronic high dose of morphine (14% of control). Furthermore, a similar degree of tolerance to post-ECS analgesia was seen following either repeated ECS in drug-naive animals or the chronic administration of the high dose of morphine. Thus, the partial naloxone blockade of ECS analgesia and the more substantial attenuation of post-ECS analgesia seen in morphine-tolerant animals provide different estimates of opioid involvement in these phenomena. It is proposed that these results may demonstrate the involvement of different opioid systems in analgesia and catalepsy and it is suggested that more than one opioid system may also be involved in post-ECS analgesia.

Behavioral classification of excitatory amino acid receptors in mouse spinal cord

Intrathecal injections of excitatory amino acid (EAA) agonists to the spinal cord of mice produces behavioral activation manifest as biting and scratching of the hindquarters. The dose-response relationship of EAA (N-methyl-D-aspartate (NMDA), kainate, quisqualate and glutamate)-induced activation revealed qualitative and quantitative differences in their pattern of action, suggesting that these agonists act at distinct receptors. Evaluation of the blockade of EAA-induced bites by a series of antagonists: DL-2-amino-5-phosphonovalerate (APV), gamma-D-glutamyl glycine (DGG), kynurenate and glutamylaminomethylsulphonate (GAMS), indicated that selective activation of the NMDA, quisqualate and kainate receptors can be demonstrated using this behavior. The NMDA receptors could be subdivided on the basis of different sensitivity to kynurenate and APV. Antagonist-resistant components of both kainate and quisqualate action were also shown. Thus, the biting behavior induced by the administration of intrathecal EAA agonists can be used as a relatively selective behavioral tool for assessing the pharmacological profile of action of excitatory amino acid agonists and antagonists in the spinal cord.

Pro- and anticonvulsant action of morphine in rats.

Rats were pretreated either with saline or with various doses of morphine. Thirty minutes following this pretreatment animals received an injection of either naltrexone (5 mg/kg) or saline. Motility was measured following the second injection. All animals then received 40 mg/kg pentamethylenetetrazol (PTZ). Morphine, but not naltrexone, showed anticonvulsant action by increasing the latencies to the first preclonic jerk and seizure onset. In addition, morphine tended to shorten seizure duration, whereas naltrexone tended to lengthen it. However, at the most effective anticonvulsant dose morphine-treated animals showed significantly more covulsive seizures than did the saline-treated controls. The continuation of these multiple seizures was blocked by naltrexone. At doses which did not lower preseizure motility but rather increased it, morphine significantly embraced the duration of the behavioral post-ictal depression (PID). Naltrexone, though effecting preseizure motility when administered after morphine, did not effect PID. These results are taken as evidence, that morphine possesses both pro- and anticonvulsant properties, depending on the prior occurrence of a PTZ-induced seizure. The possibility that seizures cause increased sensitivity of the organism to morphine is discussed.