Affecting Motor Function

The smallest structural unit of skeletal musculature is the striated muscle fiber. It contracts in response to an impulse of its motor nerve. In executing motor programs, the brain sends impulses to the spinal cord. These converge on a-motoneurons in the anterior hom of the spinal medulla. Bundled in motor nerves, efferent axons course to skeletal muscles. Simple reflex contractions to sensory stimuli, conveyed via the dorsal roots to the motoneurons, occur without participation of the brain. Neural circuits that propagate afferent impulses into the spinal cord contain inhibitory intemeurons. These serve to prevent a possible overexcitation of motoneurons (or excessive muscle contractions) due to the constant barrage of sensory stimuli. 

Neuromuscular transmission (B) of motor nerve impulses to the striated muscle fiber takes place at the motor end plate. The nerve impulse liberates acetylcholine (ACh) from the axon terminal. ACh binds to nicotinic cholinoceptors at the motor end plate. This causes depolarization of the postsynaptic membrane, which in turn elicits a propagated action potential (AP) in the surrounding sarcolemma. The AP triggers a release of Ca2+ from its storage organelles, the sarcoplasmic reticulum (SR), within the muscle fiber the rise in Ca2+ concentration induces a contraction (electromechanical coupling). Meanwhile, ACh is hydrolyzed by acetylcholinesterase (p. 104) excitation of the end plate subsides. If no AP follows, Ca2+ is taken up again by the SR and the myofilaments relax. 

The convulsants toxins tetanus toxin (cause of wound tetanus) and strychnine, diminish the ef cacy of interneuronal synaptic inhibition mediated by the amino acid glycine (A). As a consequence of an unrestrained spread of impulses in the spinal cord, motor convulsions develop. Spasms of respiratory muscle groups endanger life. 

Botulinus toxin from Clostridium botuli-num is the most potent poison known. The estimated lethal dose for 50% of an exposed human population is 1 / 10 9 g/kg (i.e., about 75 nanograms for an adult individual). The toxin, a zinc endopeptidase, blocks exo-cytosis of ACh in motor (and also parasympathetic) nerve endings. Death is caused by paralysis of respiratory muscles. 

A pathological rise in serum Mg2+ levels also causes inhibition of neuromuscular transmission. 

---

Cammarato A, Dambacher CM, Knowles AE, et al. (2008) Myosin transducer mutations differentially affect motor function, myofibril structure, and the performance of skeletal and cardiac muscles. Mol Biol Cell 19, 553-62. 

Similar results were observed when laboratory rats were treated with mixtures of the same pesticides. Mixtures of DEET and promethrin, DEET and PB, promethrin or all three and PB led to locomotor and sensorimotor dysfunctions as well as significant decreases in AChE activities in the brains of laboratory animals treated with these mixtures. Individually, the three pesticides did not affect motor functions or have any inhibitory effect on plasma or brain cholinesterase activitiesJ23 ... 

Many tests have been devised to provide quantitative measures of behavioral disturbances caused by neurotoxic chemicals. Tests have been devised that assess the effects of chemicals on four behavioral functions (D Mello 1992). These are sensory, cognitive, motor, and affective functions. However, because the entire nervous system tends to work in an integrated way, these functions are not easily separable from one another. For example, the outcome of tests focused on sensory perception by rats may be influenced by effects of the test chemical on motor function. 

Tetanus occurs when Cl. tetani, ubiquitous in the soil and faeces, contaminates wounds, especially deep puncture-type lesions. These might be minor traumas such as a splinter, or major ones such as battle injury. At these sites, tissue necrosis and possibly microbial growth reduce the oxygen tension to allow this anaerobe to multiply. Its growth is accompanied by the production of a highly potent toxin which passes up peripheral nerves and diSuses locally within the central nervous system. It acts like strychnine by affecting normal function at the synapses. Since the motor nerves of the brain stem are the shortest, the cranial nerves are the first affected, with twitches of the eyes and spasms of the jaw (lockjaw). 

PCP affects the sensorium, behavior, and vital signs, and it may affect motor and autonomic functions. Hypertension and nystagmus... 

Tvedt B, Edland A, Skyberg K, et al. 1991a. Delayed neuropsychiatric sequelae after acute hydrogen sulfide poisoning Affection of motor function, memory, vision and hearing. Acta Neurol Scand 84 348-351. 

Ferguson and Bowman 1990 Gilbert and Rice 1987 Hopper et al. 1986 Krasovskii et al. 1979 Levin et al. 1988 Massaro and Massaro 1987 Overmann 1977 Rice 1985a). It appears that animals are affected at roughly the same blood lead levels as humans. Measured neurotoxic effects in animals include significantly delayed motor function and reflexes, decreased performance on learning tasks, and impaired spatial discrimination. Additional animal studies are needed to investigate the neurotoxic effects of subchronic inhalation exposures to establish external dose-effect relationships. 

Paralysis Inhibition or loss of motor function may be characterized by affected portion of the body. 

Peripheral nerve functions are not affected equally by local anesthetics. Loss of sympathetic function usually is followed by loss of temperature sensation sensation to pinprick, touch, and deep pressure and last, motor function. This phenomenon is called differential blockade. Differential blockade is the result of a number of factors, including the size of the nerve, the presence and amount of myelin, and the location of particular fibers within a nerve bundle. For conduction to be effectively blocked, the local anesthetic must exert its effects over the distance between several nodes of Ranvier. Since the smallest nerves (C fibers) have no myelin, they can be most easily blocked thus, sympathetic functions often are blocked soon after a local anesthetic is applied to a particular nerve bundle. Small myelinated nerves have correspondingly short distances between nodes of Ranvier and therefore are often blocked next. These nerves subserve temperature and sharp pain sensation. Larger nerves then become blocked, accounting for the loss of function up to and including motor innervation. 

In very large quantities, DXM can cause effects similar to those of ketamine and PCP because these drugs affect similar sites in the brain. These effects can include impaired motor function, numbness, nausea/vomiting, and increased heart rate and blood pressure. On rare occasions, hypoxic brain damage—caused by severe respiratory depression and a lack of oxygen to the brain—has occurred due to the combination of DXM with decongestants often found in the medication. 

Topical anesthesia has also been used to improve motor function in some patients with skeletal muscle hypertonicity resulting from a cerebrovascular accident (CVA) or head trauma.53 In this situation, a local anesthetic (e.g., 20% benzocaine) can be sprayed on the skin overlying hypertonic muscles, and then various exercises and facilitation techniques can be performed to increase and improve mobility in the affected limbs. The rationale of this treatment is that it temporarily decreases abnormal or excessive excitatory feedback of cutaneous receptors on efferent motor pathways so that normal integration and control of motor function can be reestablished. Preliminary evidence has suggested that repeated application of this... 

In situations where central neural blockade is used, therapists should be especially aware that sensation might be diminished below the level of epidural or spinal administration. Decreased sensation to thermal agents and electrical stimulation will occur when the central block is in effect.10 Likewise, motor function may be affected in the lower extremities when local anesthetics are administered spinally or epidural-ly.10 Hence, therapists should test sensation and motor strength before applying any physical agents or attempting ambulation with patients who have received some type of central neural blockade using a local anesthetic. 

Botulinum toxin injection has been documented as a means to control severe spasticity in various clinical situations. This intervention, for example, can help remove spastic dominance in certain patients so that volitional motor function can be facilitated. For example, judicious administration of botulinum toxin can result in improved gait and other functional activities in selected patients with cerebral palsy, stroke, or traumatic brain injury.7,36,49,78 Even if voluntary motor function is not improved dramatically, reducing spasticity in severely affected muscles may produce other musculoskeletal benefits. For example, injection of botulinum toxin can reduce spasticity so that muscles can be stretched or casted more effectively, thus helping to prevent joint contractures and decreasing the need for surgical procedures such as heel-cord lengthening and adductor release.12,98... 

Dopamine A neurotransmitter located in the central nervous system (CNS) that is important in motor control as well as in certain aspects of behavior. The presence of endogenous or exogenous dopamine in the periphery also affects cardiovascular function. 

One additional point of consideration when interpreting the above studies is to note that in pre-clinical models, retigabine and to a lesser extent ICA-27243 also affect locomotor activity. However, in general there is a separation between the MED for efficacy in pain models and the lowest dose which shows locomotor side-effects, supporting the hypothesis that Kv7 agonists are effective in pre-clinical models of pain independent of inhibiting motor function. These results in conjunction with those reported in studies on sensory neurons indicate that Kv7 activation inhibits nociceptive neuronal firing and behavioral endpoints in pre-clinical pain models. 

---