Effect of 6-hydroxydopamine-induced lesions to ascending and descending noradrenergic pathways on morphine analgesia.
A systematic study of the role of descending, ascending and both aspects of noradrenergic pathways in the analgesic action of morphine was undertaken. The neurotoxin 6-hydroxydopamine (6-OHDA) was microinjected into the medullary A1 region, the dorsal bundle (DB), locus coeruleus (LC) or the cerebral ventricles (i.c.v.) to deplete noradrenaline (NA) in these pathways. The analgesic effect of systemically administered morphine 7-15 mg/kg was generally tested 7-12 days postlesion, and at the end of the experiment, brain and spinal cord regions were extracted and NA and dopamine (DA) measured by HPLC to verify the placement of lesions. Medullary A1 lesions profoundly depleted spinal cord NA with only a modest effect on mesencephalic levels. Such lesions inhibited the effect of morphine in a pressure test, but not in thermal tests (tail flick and hot plate) for nociception. DB lesions reduced NA in the cortex, hippocampus, hypothalamus and midbrain, but not in the spinal cord, and potentiated morphine analgesia in thermal tests for nociception. DA levels in the striatum were normal in this group. In another group where different stereotaxic coordinates were used, the pattern of NA depletion was similar, but DA levels in the striatum were reduced. In this group, potentiation of analgesia was no longer observed. LC lesions depleted NA throughout the neuraxis and potentiated morphine analgesia in both pressure and thermal tests for nociception. I.c.v. 6-OHDA depleted NA to a comparable degree to LC lesions, but striatal DA levels also were reduced and potentiation of morphine analgesia was not observed. These results indicate that central NA pathways are critical to the expression of morphine analgesia. The effect of depletion of NA in both ascending and descending aspects is the same as depletion in ascending pathways only, suggesting that this pathway is an important mediator of morphine analgesia. Simultaneous depletion of DA in the striatum can reverse the potentiating action of NA depletion indicating a critical role for DA with respect to NA pathways and mechanisms of analgesia.
D000698:Analgesia; D000818:Animals; D001921:Brain / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism / Q000502:physiology; D004525:Efferent Pathways / Q000378:metabolism; D006892:Hydroxydopamines; D008125:Locus Coeruleus / Q000378:metabolism / Q000502:physiology; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism / Q000502:physiology; D009020:Morphine / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism* / Q000502:physiology; D016627:Oxidopamine; D010146:Pain / Q000503:physiopathology*; D051381:Rats; D011919:Rats, Inbred Strains; D013116:Spinal Cord / Q000187:drug effects*
D006892:Hydroxydopamines; D009020:Morphine; D016627:Oxidopamine; D004298:Dopamine; D009638:Norepinephrine