Pharmacological aids to locomotor training after spinal injury in the cat

Abstract

This Topical Review summarizes some of the work we have done mainly in the cat using agonists and antagonists of various neurotransmitter systems injected intravenously or intrathecally to initiate or modulate the expression of hindlimb locomotion after a spinal lesion at T13. The effects of the same drugs are compared in various preparations: complete spinal, partial spinal or intact cats. This has revealed that there can be major differences in these effects. In turn, this suggests that although the locomotor rhythm might normally be triggered and modulated by the activation of a variety of receptors (noradrenaline, serotonin, glutamate), after spinalization there appears to be a predominance of glutamatergic mechanisms. Recent work also suggests that, in the cat, the integrity of the midlumbar segments is crucial for the expression of spinal locomotion. Taken together, this work raises some hope that a targeted pharmacotherapy with better understood drugs and mode and locus of delivery could become a clinical reality.

Figure 1. Effects of the noradrenergic antagonist yohimbine and the NMDA antagonist AP5 on locomotion in the intact cat

A, D and G, outlines of cats drawn from video recordings; from left to right, the hindlimb positions are at left foot contact, onset of right swing, right foot contact, and onset of left swing, respectively. B, E and H, EMGs of the hindlimb muscles during treadmill locomotion in the same sequence. RSt, right semitendinosus; LSrt, left sartorius; RSrt, right sartorius; LVL, left vastus lateralis; LGL, left gastrocnemius lateralis; RGL, right gastrocnemius lateralis; LGM, left gastrocnemius medialis; RGM, right gastrocnemius medialis; C, F and I, duty cycles. A-C, cat in the control state walking at 0.4 m s⁻¹ before drug injection. D-F, 10 min after yohimbine (1600 μg per 100 μl i.t.), at 0.2 m s⁻¹. The cat had major walking abnormalities characterized by difficulty in maintaining lateral stability of the hindquarters and asymmetry of hindlimb stepping leading to the turning of the hindquarters to one side or the other. The duty cycle is only indicated for the period where foot contacts could clearly be identified. G-I, same cat, 50 min after AP5 (500 μg per 100 μl i.t.), at 0.4 m s⁻¹. The cat shows a reduced weight support leading to a crouched position of the hindquarters and a significant foot drag of both hindlimbs at the beginning of the swing phase.

Figure 2. Effects of the antagonists yohimbine and AP5 on locomotion in the late spinal cat

Same display as Fig. 1, but all at 0.4 m s⁻¹ and for a different cat. A-C, 73 days after spinalization but before any drug administration. The locomotor pattern was characterized by full weight support of the hindquarters, plantar foot placement and coordinated rhythmic activation of flexor and extensor muscles. D-F, 7 min post-yohimbine (1600 μg per 100 μl i.t.), there were no major changes in the locomotor pattern. G and H, same cat but now 131 days after spinalization, 34 min after AP5 (500 μg per 100 μl i.t.) administration. The same dose that produced minor deficits in an intact cat (see Fig. 1G-I), now caused a total block of the locomotor pattern in this spinal cat. This effect lasted 1 h and the spinal cat gradually recovered locomotion in about 3-4 h. LSt, left semitendinosus.

Figure 3. Intraspinal microinjections of a noradrenergic blocker, yohimbine, at two spinal levels

EMG recordings of an adult decerebrated cat with a large lumbar laminectomy and mounted over a treadmill. The cat was spinalized at T13, 6 days earlier. A, 10 min after i.v. clonidine (500 μg kg⁻¹). B, 45 min after intraspinal injections of yohimbine (8 mg ml⁻¹). There were 8 injections of 2 μl each at 2 mm deep paramedially, all in the L6 segment. The clonidine injection was performed 65 min previously. C, 3 min after 8 intraspinal injections of yohimbine (8 mg ml⁻¹ and 2 μl per injection) at 2 mm deep paramedially in L4 segment. The i.v. clonidine was given 126 min before and the injections of yohimbine in the L6 segment, shown in B, were made 106 min before. RVL, right vastus lateralis; RTA, right tibialis anterior; LTA, left tibialis anterior.

Figure 4. Laminar and segmental distribution of α₂ noradrenergic receptors in control and spinal cats

The graphs show the average amount of specific [³H]idazoxan binding in lamina II (A) and lamina V (B) as a function of the lumbosacral spinal segmental (L1-S3) in 2 intact and in 2 short-term (30 days) spinal cats. Note that following spinalization, as indicated by the thick continuous line, an α₂ receptor up-regulation was seen from L2 to L5, while a down-regulation was seen from L7 to S3 segments.