Lack of evidence for the size principle of selective vulnerability of axons in toxic neuropathies. I. The effects of subcutaneous injections of 2,5-hexanedione on behavior and muscle spindle function.

2,5-Hexanedione (HD) produces a central-peripheral distal axonopathy. It has been suggested that agents which produce this type of axonopathy show a predilection to the largest diameter fibers. This has been based primarily on morphological data. However, electrophysiological evidence and some clinical and morphological data suggest that this may not be the case. In particular, in acrylamide neuropathy, muscle spindle primary afferents do not show this selectivity, as well as autonomic fibers. This study was carried out to determine whether the largest diameter axons were selectively vulnerable to HD. We found that subcutaneous injections of HD in cats produced a dose-dependent increase in behavioral deficits such as contact placing, stepping, and locomotion. There was also a dose-dependent decrease in the position sensitivity of muscle spindle primary and secondary endings. However, the secondary endings, which are innervated by smaller axons, were affected prior to the primary endings. Also, the velocity sensitivity of the primary endings was depressed at a similar time frame as the position sensitivity of these same endings. These data are consistent with the hypothesis that the caliber of the axon is not the only determinant of the selective vulnerability of axons in distal axonopathy.

Effects of 2,5-hexanedione on deefferented muscle spindle position sensitivity.

2,5-Hexanedione (HD) produces a neurofilamentous axonpathy in humans and experimental animals. The present study was carried out to determine the time course of the effects of HD on muscle spindle position sensitivity to permit comparisons with similar effects of other toxicants which produce a neurofilamentous axonopathy. Cats were administered HD either via their drinking water or via osmotic minipumps. Muscle spindle position sensitivity was tested after a total HD dose of 2.43 or 4.85 g/kg via the drinking water or 0.96, 1.91, or 4.78 g/kg via an osmotic minipump. The position sensitivities of both primary and secondary endings were depressed regardless of the route of administration. However, secondary muscle spindle afferents in the animals intoxicated with HD via the minipumps were affected to a greater extent than primary muscle spindle afferents at all doses studied. These data show that HD alters muscle spindle function and lends support to the suggestion that the largest diameter fibers are not the most vulnerable to HD.

Primary afferent terminal function following acrylamide: alterations in the dorsal root potential and reflex.

The dorsal root potential (DRP) and the dorsal root reflex (DRR) were studied in acrylamide (ACR)-induced axonopathy to determine the nature and extent of primary afferent terminal (PAT) dysfunction. Cats were administered 30 mg/kg/day ACR for either 5 (ACR 5D) or 10 (ACR 10D) days. The day after the last injection, the spinal cord as isolated in situ and the DRP and DRR were elicited. It was found that only 21% of the ACR 10D animals exhibited a DRP. Furthermore, in that 21%, the DRP appeared to degrade over distance differently from the control group. There was no change in the DRP evoked in the ACR 5D group. ACR affected the DRR when evoked from the cutaneous sural nerve (SU) to a greater extent than when evoked from the medial gastrocnemius (MG) nerve. A SU-evoked DRR could not be elicited in any of the animals in the ACR 10D group and in only 20% of the ACR 5D group. There was no difference in the ability to elicit a MG-evoked DDR in either ACR-treated group when compared to control. However, the maximum-evoked area under the DRR elicited from the MG nerve was significantly smaller in the ACR-treated groups than in control. These data show that ACR does indeed impair PAT function. ACR preferentially affects the PAT processing of the SU when compared to the MG nerve, which may indicate that the selective vulnerability of the largest diameter fibers to ACR is not necessarily true.