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Subcutaneous Administration of Muscarinic Antagonists and Triple-Immunostaining of the Levator Auris Longus Muscle in Mice
Published on: September 8, 2011
Cholinergic inputs to motoneurons in the spinal cord augment focal muscle spasticity in rodents
Patrik Meglić1, Petra Šoštarić1,2, Eirini Tsape3
1Laboratory of Molecular Neuropharmacology, Department of Pharmacology and Croatian Institute of Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia.
Background And Purpose:
Cholinergic premotor inputs to motoneurons support high levels of motor output when required. However, the possible role of these inputs in pathologically elevated muscle tone has not been characterised. To address this, we examined the modulatory effect of spinal acetylcholine (ACh) on experimental spastic paralysis.
Experimental Approach:
Rats were injected with tetanus neurotoxin (TeNT, 33-100 pg, im) into gastrocnemius to induce sustained rigid hind-paw extension and resistance to passive ankle flexion. The effects of spinal ACh on experimental hypertonia were probed by lumbar intrathecal application of the AChE inhibitor neostigmine (NEO) or a muscarinic M2 receptor antagonist (AQ-RA 741). Effects of NEO on extracellular ACh were measured in the facial nucleus after TeNT (33 pg) or botulinum toxin A (BoNT/A, 2 U) injection into the rat whisker pad. The intensity of TeNT-evoked hindlimb hypertonia (10 pg, im) was assessed in mice with genetic ablation of cholinergic C bouton source interneurons (V0C interneurons).
Key Results:
NEO augmented the severity of TeNT-evoked hypertonia, whereas AQ-RA 741 attenuated it. Local perfusion of NEO caused a BoNT/A-sensitive increase in extracellular ACh concentration. The involvement of cholinergic C boutons was corroborated by reduced hypertonia following TeNT challenge (10 pg, im) in V0C-ablated mice.
Conclusions And Implications:
Our results suggest that spinal cholinergic transmission, associated with vesicular ACh release and M2 signalling at C boutons, exacerbates experimental spastic paralysis. We reveal a new role for endogenous spinal ACh, with implications for developing new therapeutic approaches to treat spasticity and hyperkinetic movement disorders.
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