Rat Model Of Peripheral Mononeuropathy Research Articles

Guanosine Prevents Thermal Hyperalgesia in a Rat Model of Peripheral Mononeuropathy

It is well known that adenine-based purines exert multiple effects on pain transmission. Less attention has been given, however, to the antinociceptive effects of guanine-based purines. The aim of this study was to investigate the effects of intraperitoneal administration of guanosine on a rat model of peripheral mononeuropathy. Additionally, investigation of the mechanism of action of guanosine, its general toxicity and measurements of central nervous system purine levels were performed. Rats received an intraperitoneal administration of vehicle (0.1 mM NaOH) or guanosine (up to 120 mg.kg(-1)) in an acute or chronic regimen. Guanosine significantly reduced thermal hyperalgesia on the ipsilateral side of the sciatic nerve ligation. Additionally, guanosine prevented locomotor deficits and body weight loss induced by the mononeuropathy. Acute systemic administration of guanosine caused an approximately 11-fold increase on central nervous system guanosine levels, but this effect was not observed after chronic treatment. Chronic guanosine administration prevented the increase on cortical glutamate uptake but not the decrease in spinal cord glutamate uptake induced by the mononeuropathy. No significant general toxicity was observed after chronic exposure to guanosine. This study provides new evidence on the mechanism of action of guanine-based purines, with guanosine presenting antinociceptive effects against a chronic pain model. This study provides a new role for guanosine: chronic pain modulation. Guanosine presents as a new target for future drug development and might be useful for treatment of neuropathic pain.

Dextromethorphan potentiates the effect of morphine in rats with peripheral neuropathy.

Neuropathic pain responds poorly to opioids. We now report that combination of systemic morphine (2 mg/kg) and dextromethorphan (45 mg/kg), a clinically available antitussive with NMDA-antagonist properties, markedly alleviated mechanical and cold allodynia-like behavior in a rat model of peripheral mononeuropathy. Neither drug produced a significant effect on its own at these doses. The anti-allodynic effect of morphine plus dextromethorphan was reversed by naloxone. The present results suggest that a combination of NMDA-antagonist and opiates might be effective in treating neuropathic pain. Furthermore, the effect of this drug combination is mainly mediated via opioid receptors.

Preemptive Intrathecal Ketamine Delays Mechanical Hyperalgesia in the Neuropathic Rat

We studied the effect of preemptive intrathecal ketamine administration on the development of mechanical hyperalgesia in a rat model of mononeuropathy.Rats given intrathecal ketamine 1 mg/kg or normal saline were subsequently rendered neuropathic by placing four loose ligatures around the sciatic nerve. The onset of resultant hyperalgesia was evaluated using von Frey monofilaments. Preemptive ketamine significantly slowed the onset of mechanical hyperalgesia at both 2.35 g (P < 0.04) and 4.19 g (P < 0.05) thresholds through the third postoperative day but did not alter the ultimate degree of hyperalgesia in either severity or frequency in this model. We conclude that ketamine delayed the onset, but failed to prevent the development of, mechanical hyperalgesia in a rat model of peripheral mononeuropathy. Implications: Pain in response to light touch may follow nerve injury. Prevention of this complication would be clinically useful. Ketamine, an anesthetic, was administered spinally to rats before nerve injury in an attempt to prevent the development of chronic pain. Hypersensitivity to light touch was delayed by preemptive ketamine. (Anesth Analg 1997;86:557-60)

Preemptive intrathecal ketamine delays mechanical hyperalgesia in the neuropathic rat.

We studied the effect of preemptive intrathecal ketamine administration on the development of mechanical hyperalgesia in a rat model of mononeuropathy. Rats given intrathecal ketamine 1 mg/kg or normal saline were subsequently rendered neuropathic by placing four loose ligatures around the sciatic nerve. The onset of resultant hyperalgesia was evaluated using von Frey monofilaments. Preemptive ketamine significantly slowed the onset of mechanical hyperalgesia at both 2.35 g (P < 0.04) and 4.19 g (P < 0.05) thresholds through the third postoperative day but did not alter the ultimate degree of hyperalgesia in either severity or frequency in this model. We conclude that ketamine delayed the onset, but failed to prevent the development of, mechanical hyperalgesia in a rat model of peripheral mononeuropathy. Pain in response to light touch may follow nerve injury. Prevention of this complication would be clinically useful. Ketamine, an anesthetic, was administered spinally to rats before nerve injury in an attempt to prevent the development of chronic pain. Hypersensitivity to light touch was delayed by preemptive ketamine.

Bilaterally enhanced dorsal horn postsynaptic currents in a rat model of peripheral mononeuropathy

Surface compound potentials were recorded from the surgically exposed lumbar spinal cord in anaesthetized rats which had had one sciatic nerve loosely ligatured 12–15 days previously, resulting in unilateral allodynia and hyperalgesia, as assessed behaviourally. These cord dorsum potentials were recorded in response to electrical stimulation of the ligatured and non-ligatured sciatic nerve, respectively, on both the ipsi- and contralateral side with respect to the stimulated nerve. Compared to potentials produced by stimulation of the non-ligatured sciatic nerve, electrical stimulation of large diameter fibres proximal to the ligatures resulted in a smaller afferent fibre input arriving at the spinal cord. However, larger net postsynaptic currents in the contralateral dorsal horn and a larger net post-synaptic current per unit of afferent fibre input were found in the ipsilateral and contralateral spinal cord. Such changes may result from structural changes or increased synaptic efficacy in the dorsal horn following peripheral nerve injury.

Antinociceptive effect of a κ-opioid receptor agonist that minimally crosses the blood-brain barrier (ICI 204448) in a rat model of mononeuropathy

The antinociceptive effect of intraplantar (i.pl.) ICI 204448 (( R,S)- N-[2-( N-methyl-3,4-dichloro-phenylacetamido)-2-(3-carboxyphenyl)-ethyl]pyrrolidine hydrochloride)) (20, 30, 40 and 50 μg), a κ-opioid receptor agonist which has limited access to the central nervous system, was studied in a well-established rat model of peripheral mononeuropathy produced by moderate constriction of the sciatic nerve. Vocalization thresholds to paw pressure were used as a nociceptive test. On the injected nerve-injured paw, ICI 204448 at 20 and 30 μg had no significant effect, but higher doses (40 μg) produced a significant antinociceptive effect, which plateaued at 50 μg. By contrast, no antinociceptive effect was observed on the contralateral paw. The effect of ICI 204448 (40 μg) was significantly antagonised by the specific κ-opioid receptor antagonist nor-binaltorphimine (20 and 30 μg), when co-injected in the nerve-injured paw.

Evidence for a peripheral component in the enhanced antinociceptive effect of a low dose of systemic morphine in rats with peripheral mononeuropathy

In a rat model of peripheral mononeuropathy produced by moderate constriction of the sciatic nerve, we have shown that various i.v. doses of morphine and selective opioid agonists produce potent and long-lasting antinociceptive effects on the vocalization threshold to paw pressure. For all the opioids, the antinociceptive effects were more marked for the paw on the nerve-injured side (nerve-injured paw) than for the sham-operated paw. One contributory mechanism could be a peripheral action of the opioid agonists in the nerve-injured paw. This hypothesis was tested in the present study, using systemic morphine and low doses of local naloxone or its quaternary salt naloxone methiodide, exhibiting peripherally acting antagonist properties. The effects of escalating doses of naloxone (0.5-2 microgram injected i.v. or intraplantar into the nerve-injured paw) or naloxone methiodide (5-30 micrograms into the nerve-injured paw) on the antinociceptive effect of morphine (1 mg/kg i.v.) were evaluated using the vocalization threshold to paw pressure in neuropathic rats at two weeks after placing ligatures, a time when the behavioural pain-related disorders have reached a maximum.(ABSTRACT TRUNCATED AT 250 WORDS)

Responses of neurons in the ventrolateral orbital cortex to noxious cutaneous stimulation in a rat model of peripheral mononeuropathy

The responses of ventrolateral orbital cortex neurons to noxious cold pressor were compared in rats with loose ligatures tied around their sciatic nerve with those in rats in which the sciatic nerve was exposed but not ligated. In ligated rats more cells responded to cold pressor and their average afterdischarges were longer. There were no differences in the background firing rate or the magnitude of response to the cold pressor between the two groups.

The Ganglioside GM1 Decreases Autotomy but Not Substance P Depletion in a Peripheral Mononeuropathy Rat Model

The effect of the ganglioside GM1 on autotomy, a nociceptive behavioral marker for neuropathic pain, and substance P depletion was determined in a rat model of peripheral mononeuropathy, sciatic cryoneurolysis (SCN). SCN is produced by the application of a cryoprobe to the common sciatic nerve using a freeze-thaw-freeze cycle. Due to structural sparing of the nerve, regenerative processes are not precluded. After this peripheral nerve insult, behavioral and neurochemical changes occur that support the use of SCN as a neuropathic pain model. These changes include: autotomy with coincident transient weight loss and paling of eye color suggestive of increased sympathetic activity, spontaneous nociceptive behaviors, touch-evoked allodynia, prolonged mechanical allodynia, ipsilateral decrease of immunoreactive substance P, and increases in spinal cord dynorphin expression. Incidence and severity of autotomy were assessed after the intraperitoneal administration of GM1 (1, 10, and 20 mg/kg) or saline injected daily for 2 days before SCN, the day of surgery, and for 14 days after surgery. In a subset of two rats from each treatment group, transcardiac perfusion was performed and spinal cords were processed for substance P immunoreactivity. GM1 at 10 and 20 mg/kg doses significantly attenuated autotomy as compared with saline-treated rats (P = 0.007 and 0.0001, respectively). However, GM1, at the doses studied, failed to alter the spinal substance P depletion 21 days after SCN. These results indicate that the ganglioside GM1 may have a role in the clinical management of neuropathic pain after peripheral nerve injury.

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.

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.

Behavioural evidence that systemic morphine may modulate a phasic pain-related behaviour in a rat model of peripheral mononeuropathy

In a model of peripheral mononeuropathy produced by 4 ligatures around the sciatic nerve, we investigated the effects of various i.v. doses of morphine on the vocalization thresholds elicited by paw pressure and compared the effects obtained with the same doses in normal rats. In neuropathic rats, morphine (0.1 and 0.3 mg/kg) produced a significant analgesic effect on the lesioned hind paw, maximum at 15 min post injection with a recovery at 20–25 min. For doses of 0.6 and 1 mg/kg, a modification of the kinetics was observed, with maximum effect at 20–30 min post injection and a recovery at 50–80 min. An analgesic effect was also observed on the unlesioned side, significantly less potent than that observed on the lesioned paw. The effect of 1 mg/kg morphine was almost totally reversed by a 0.1 mg/kg dose of systemic naloxone. The effects induced by the successive doses of morphine on the lesioned paw appeared higher than in normal rats (maximum vocalization thresholds (% of control) following 1 mg/kg morphine ( N = 12) were 193.92 ±6.57% versus 154 ± 3.5% in normal rats N = 3), whereas they were comparable to those obtained from the sham-operated paw. The present data clearly show that morphine induces potent antinociceptive effects in a rat model of neuropathy, which seems to contradict the classical view that neuropathic pain is opioid resistant. Some possible pathophysiological mechanisms are discussed.

The bidirectional dose-dependent effect of systemic naloxone is also related to the intensity and duration of pain-related disorders: a study in a rat model of peripheral mononeuropathy

In an experimental model of mononeuropathy in the rat, created by 4 ligatures around the sciatic nerve, i.v. naloxone 1 week after surgery induces bidirectional effects (antinociceptive effects at very low doses, hyperalgesic effects with high doses). Using the same nociceptive test (vocalization thresholds to paw pressure), the activity of the same doses of naloxone (3 μg/kg, and 1 mg/kg) was investigated 2 weeks after sciatic ligation, when the behavioural pain-related disorders are at a maximum. Three μg/kg naloxone produced a significant antinociceptive effect on the lesioned and non-lesioned paw, which was clearly related to the degree as well as to the duration of pain-related signs in the rat. By contrast, the high dose of naloxone did not induce a mean significant effect when tested on either paw; however, it elicited a potent hyperalgesic effect in those rats which had recovered from hyperalgesia at this 2 week time point after the sciatic injury.