Genetic differences in neuropathy and opioid responses in rats

The studies examined mechanisms and treatments of experimental neuropathic pain with particular emphasis on the differences between rat strains and sub-strains in basal nociceptive sensitivity, development of neuropathic behaviors and sensitivity to opioid analgesia. In order to study the mechanisms that mediate mechanical allodynia (touch-evoked pain) following ischemic nerve injury to the sciatic nerve in rats, the myelinated primary afferents have been examined in the injured and intact nerves. Although the properties of myelinated afferents after nerve injury were not different from that of control, spontaneous ectopic discharges were observed in damaged myelinated fibers which may be involved in triggering and maintaining central sensitization causing touch-evoked, A(beta)fiber mediated allodynia. Spontaneously Hypertensive Rats (SHRs) are significantly less sensitive to nociceptive stimulation and less susceptible to the development of mechanical hypersensitivity compared to Sprague-Dawley rats (SD).

The present studies revealed that the properties of myelinated primary afferents in SHRs are not different from those of SDs. Therefore, the reduced development of mechanical hypersensitivity in SHRs is not related to the properties of cutaneous mechanoreceptors, but may be due to central mechanisms. Chronic opioid treatment leads to tolerance. We showed that development of tolerance to the anti-allodynic effect of methadone was significantly delayed compared to morphine in neuropathic rats and there is an incomplete cross-tolerance between the two opioids. This may be related to higher intrinsic activity of methadone or its NMDA receptor antagonistic properties. Since the development of neuropathic pain behaviors differ between the two sub-strains of SD rats, we tested the anti-nociceptive effect of different opioids, in order to study the relationship between opioid analgesia and the development of neuropathic pain. SD-Möllegaard (SD-MÖ) rats are more prone to develop neuropathic pain-like behaviors compared to SD-B&K Universal (SD-BK), and less sensitive to the anti-nociceptive effect of morphine and methadone. We showed, that different levels of activity of NMDA receptors and/or differential morphine metabolism may underlie the behavioral differences.

List of scientific papers

I. Bulka A, Hao JX, Wiesenfeld-Hallin Z (2002). Response characteristics of cutaneous mechanoreceptors in neuropathic rats. Neurosci Lett. 317(2): 89-92.
https://pubmed.ncbi.nlm.nih.gov/11755247

II. Bulka A, Wiesenfeld-Hallin Z (2003). Comparison of response characteristics of cutaneous mechanoreceptors in normal and neuropathic Sprague-Dawley and spontaneously hypertensive rats. Neurosci Lett. 340(1): 61-4.
https://pubmed.ncbi.nlm.nih.gov/12648759

III. Bulka A, Plesan A, Xu XJ, Wiesenfeld-Hallin Z (2002). Reduced tolerance to the anti-hyperalgesic effect of methadone in comparison to morphine in a rat model of mononeuropathy. Pain. 95(1-2): 103-9.
https://pubmed.ncbi.nlm.nih.gov/11790472

IV. Bulka A, Wiesenfeld-Hallin Z, Xu XJ (2002). Differential antinociception by morphine and methadone in two sub-strains of Sprague-Dawley rats and its potentiation by dextromethorphan. Brain Res. 942(1-2): 95-100.
https://pubmed.ncbi.nlm.nih.gov/12031857

V. Bulka A, Kouya PF, Bottiger Y, Svensson JO, Xu XJ, Wiesenfeld-Hallin Z (2003). Comparison of the antinociceptive effect of morphine, methadone, buprenorphine and codeine in two substrains of Sprague-Dawley rats. [Manuscript]