Possible impact of genetic differences on the development of neuropathic pain-like behaviors after unilateral sciatic nerve ischemic injury in rats.

The development of neuropathic-like behaviors following unilateral ischemic injury to the sciatic nerve was examined and compared in four rat strains: Sprague--Dawley (SD), Wistar--Kyoto (WK), spontaneously hypertensive (SHR) and Dark--Agouti (DA). We have also compared two sub-strains of SD rats supplied from two different vendors (SD-BK and SD-DK). The responses to mechanical, heat or cold stimuli of both hind paws were measured before and regularly after injury for up to 10 weeks. Spontaneous paw lifting and changes in paw posture after nerve injury were also examined. Significant differences in basal sensitivity to mechanical or heat stimulation were seen among the four rat strain studied with SHR and DA rats being less sensitive than the SD and WK rats. All strains of rats developed bilateral mechanical allodynia and ipsilateral heat hyperalgesia after photochemically-induced nerve ischemia, but the time-course and magnitude of the responses were significantly different among the strains. Again, the SHR and DA were found to be least susceptible to the development of abnormal pain-like responses. Cold allodynia occurred only in WK and SD-BK. SD-DK rats on the other hand developed more severe mechanical allodynia than SD-BK. SHR and DA rats showed less deficits in paw posture after nerve injury whereas spontaneous pain lifting, a measure of possible spontaneous pain, was comparable among all strains. Light microscopic study of the injured sciatic nerve showed comparable nerve damage in SHR, WK and two sub-strains of SD rats. The DA rats however exhibited reduced area of intraneural damage. Finally, electronmicroscopic examination revealed that damage to both myelinated and unmyelinated fibers occurred in this model in all strains. These results showed that normal sensitivity and the development of pain-like response after partial nerve injury differ substantially among different strains of rats, supporting the emerging concept that genetic factors affect pain sensitivity under normal conditions and after nerve injury. The apparent resistance of DA rats to nerve ischemia, however, may suggest that genetic factors not directly related to pain modulation also play a role in the diverse outcomes. Our results indicate that sub-strains of rats also showed variable development of neuropathic pain-like behaviors to both the modality and magnitude of the effect. Thus, controlling sub-strains is also important in experimental studies of neuropathic pain in rats.

The N-methyl-D-aspartate-receptor antagonist dextromethorphan lacks analgesic effect in a human experimental ischemic pain model.

BACKGROUND: N-methyl-D-aspartate-receptor antagonists may be useful in pain management. The aim of this study was to evaluate dextromethorphan (DEX), a commonly used oral antitussive drug with NMDA-receptor antagonistic properties, in respect of its analgesic properties as single drug and co-administered with morphine (MO) on experimental ischemic pain. In addition, the analgesic effects of another clinically available NMDA-receptor antagonist, ketamine (KET) as well as of morphine (MO) were tested as active controls. METHODS: Nineteen healthy volunteers were included in the study. Experimental ischemic pain was induced using the forearm tourniquet test. Placebo (PLAC), oral DEX (30 and 90 mg, respectively), KET (9 microg kg(-1) min(-1) i.v.), MO (0.1 mg kg(-1), i.v.) and the DEX+MO and KET+MO combinations were evaluated during eight separate experiments. Development of ischemic pain was rated by visual analog scale (VAS) every minute over 30 min and ratings were summed as sum of pain scores (SPS). RESULTS: DEX by itself did not influence SPS compared to PLAC. The DEX+MO co-administration did not enhance MO-induced analgesia. MO and KET reduced pain ratings by 27% and 39%, respectively. The KET+MO combination showed no enhancement of the analgesic effect in comparison with the respective drugs in monotherapy. CONCLUSION: DEX in clinical doses has no effect on the present acute ischemic pain model and does not influence MO-induced analgesia. Further studies on other pain modalities are needed in order to evaluate the potential use of DEX in pain treatment.

Genetic differences in the antinociceptive effect of morphine and its potentiation by dextromethorphan in rats.

The effect of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dextromethorphan on morphine-induced antinociception was studied with the hot plate test in Sprague-Dawley (SD), Wistar-Kyoto (WK), Spontaneously Hypertensive (SHR) and Dark-Agouti (DA) rats. Subcutaneous morphine at 5 mg/kg induced significant antinociception in all four rats strains. Subcutaneous dextromethorphan at 15 and 45 mg/kg, but not 5 mg/kg, significantly and dose-dependently potentiated morphine-induced antinociception in SDs, WKs and SHRs, but not in DAs. In SHRs and DAs the antinociceptive effect of morphine was followed by prolonged hyperalgesia, which was reduced (SHRs) or abolished (DAs) by dextromethorphan. These results suggest that there are significant differences among rat strains in their response to morphine and in the ability of dextromethorphan to potentiate morphine-induced antinociception. These differences are possibly of genetic origin. Moreover, these data show that morphine, at least in some strains of rats, induced a delayed and NMDA receptor-dependent hyperalgesic response, supporting the notion that administration of opiates may activate NMDA receptors, leading to reduced antinociceptive effect and the development of hyperalgesia.

Genetic differences in morphine sensitivity, tolerance and withdrawal in rats.

Significant genetic differences in the endogenous opioid system and in response to a variety of noxious stimuli are present in rodents. We now compared the response to noxious heat with the hot plate test, morphine sensitivity and the development of tolerance and dependence to morphine in spontaneously hypertensive (SHR), Wistar-Kyoto (WK) and Sprague-Dawley (SD) rats. Significant differences were observed in basal nociception among the three strains, where SHRs were hypoalgesic compared to WK and SD. The antinociceptive effect of morphine varied among strains (SD>SHR>WK) as did the rate of tolerance development (10 mg/kg morphine 2/day for 4 days) where WK>SD=SHR. SHR rats developed hyperalgesia following morphine administration during the course of tolerance development. Furthermore, although naloxone (2 mg/kg) precipitated withdrawal symptoms in all tolerant rats, the panorama of symptoms varied among the three strains. Thus, there are significant genetic differences in a variety of effect of opiates.

Comparison of ketamine and dextromethorphan in potentiating the antinociceptive effect of morphine in rats.

UNLABELLED: We compared the efficacy of two clinically available drugs with N-methyl-D-aspartate receptor antagonist properties, dextromethorphan and ketamine, in potentiating morphine-induced antinociception. Ketamine alone at 0.3-3 mg/kg had no effect on the hot plate test and at 10 mg/kg caused sedation/motor deficits. The antinociceptive effect of 5 mg/kg morphine was slightly enhanced by 1 mg/kg, but not 0.3 or 3 mg/kg, ketamine. Dextromethorphan alone at 45 mg/kg had no effect, but at 60 mg/kg caused sedation/motor deficit. At 15-45 mg/kg, dextromethorphan significantly and dose-dependently increased the magnitude and duration of morphine-induced antinociception. Dextromethorphan also potentiated morphine at doses that, by themselves, did not cause antinociception (1-2 mg/kg). IMPLICATIONS: Dextromethorphan was more effective than ketamine in potentiating morphine-induced antinociception. Dextromethorphan may thus be the drug of choice for testing the interactions between N-methyl-D-aspartate antagonists and morphine clinically.