Effects of Spinal 2-Adrenoceptor and I1-Imidazoline Receptor Activation on Hindlimb Movement Induction in Spinal Cord-Injured Mice

A partial recovery of locomotor functions has been shown in spinal cord-transected (Tx) cats after regular treadmill training and repeated administration of clonidine, an 2-adrenoreceptor agonist. However, clonidine has generally failed to show prolocomotor effects in other models (e.g., rat or mudpuppy in vitro-isolated spinal cord preparations). The reasons for this discrepancy remain unclear, but they may suggest conditionor species-specific effects induced by clonidine. This study is aimed at examining both the acute (at 6 or 41 days post-Tx) and chronic effects of repeated (once a week for one month) clonidine administration (0.25–5.0 mg/kg i.p.) on hindlimb movement generation in Tx mice (thoracic segment9/10). Locomotor-like (LM) and nonlocomotor movements (NLM) were assessed both in open-field and treadmill conditions. The results show that clonidine consistently failed, in both conditions, to induce LM and NLM at all time points even though control experiments revealed hindlimb movements steadily induced by 8-hydroxy-2-(di-N-propylamino)-tetralin (8-OH-DPAT), a serotonin receptor agonist. In turn, clonidine acutely suppressed (I1-imidazoline receptor-mediated) the frequency of spontaneously occurring LM and NLM but apparently increased spinal excitability over time, because the frequency of spontaneous LM and NLM was significantly greater in clonidine-treated (before an injection) than vehicle-treated animals after repeated administration for a few weeks. The results clearly show that clonidine can not acutely induce hindlimb movements in untrained and otherwise nonstimulated (e.g., no tail or perineal pinching) Tx mice, although repeated administration may progressively facilitate the expression of spontaneous hindlimb movements. Clonidine is generally known as a treatment against hypertension (MacDougall et al., 1970). It has been used also to treat opiate and nicotine withdrawal-related symptoms and neuropathic pain (Martin and Eisenach, 2001). In the field of spinal cord injury (SCI) research, clonidine has been reported to induce promising effects in early or late chronic spinal cord-transection (Tx) cats (Forssberg and Grillner, 1973; Barbeau et al., 1987). Indeed, combined with sensory stimulation (e.g., perineal and/or tail pinching), clonidine (i.v. or i.p. administered) was found to evoke locomotor movements or to increase functional recovery (larger movement amplitude) after regular treadmill training with body weight-support assistance in Tx cats (reviewed in Rossignol et al., 2001). Further supporting a centrally mediated action on central pattern generator (CPG) neurons, intrathecal (lumbar level) or intraspinal (L3–L4) administration of clonidine was shown to acutely (within a few minutes) evoke hindlimb stepping movements or comparable neurographic activity in Tx cats (Chau et al., 1998; Marcoux and Rossignol,