Adrenergic Receptors Modulate Motoneuron Excitability, Sensory Synaptic Transmission and Muscle Spasms After Chronic Spinal Cord Injury

Abstract

Rank MM, Murray KC, Stephens MJ, D'Amico J, Gorassini MA, Bennett DJ. Adrenergic receptors modulate motoneuron excitability, sensory synaptic transmission and muscle spasms after chronic spinal cord injury. J Neurophysiol 105: 410 -422, 2011. First published November 3, 2010 doi:10.1152/jn.00775.2010. The brain stem provides most of the noradrenaline (NA) present in the spinal cord, which functions to both increase spinal motoneuron excitability and inhibit sensory afferent transmission to motoneurons (excitatory postsynaptic potentials; EPSPs). NA increases motoneuron excitability by facilitating calcium-mediated persistent inward currents (Ca PICs) that are crucial for sustained motoneuron firing. Spinal cord transection eliminates most NA and accordingly causes an immediate loss of PICs and emergence of exaggerated EPSPs. However, with time PICs recover, and thus the exaggerated EPSPs can then readily trigger these PICs, which in turn produce muscle spasms. Here we examined the contribution of adrenergic receptors to spasms in chronic spinal rats. Selective activation of the ␣ 1A adrenergic receptor with the agonists methoxamine or A61603 facilitated Ca PIC and spasm activity, recorded both in vivo and in vitro. In contrast, the ␣ 2 receptor agonists clonidine and UK14303 did not facilitate Ca PICs, but did decrease the EPSPs that trigger spasms. Moreover, in the absence of agonists, spasms recorded in vivo were inhibited by the ␣ 1 receptor antagonists WB4010, prazosin, and REC15/2739, and increased by the ␣ 2 receptor antagonist RX821001, suggesting that both adrenergic receptors were endogenously active. In contrast, spasm activity recorded in the isolated in vitro cord was inhibited only by the ␣ 1 antagonists that block constitutive receptor activity (activity in the absence of NA; inverse agonists, WB4010 and prazosin) and not by the neutral antagonist REC15/2739, which only blocks conventional NA-mediated receptor activity. RX821001 had no effect in vitro even though it is an ␣ 2 receptor inverse agonist. Our results suggest that after chronic spinal cord injury Ca PICs and spasms are facilitated, in part, by constitutive activity in ␣ 1 adrenergic receptors. Additionally, peripherally derived NA (or similar ligand) activates both ␣ 1 and ␣ 2 adrenergic receptors, controlling PICs and EPSPs, respectively.

Adaptations in Glutamate and Glycine Content within the Lumbar Spinal Cord Are Associated with the Generation of Novel Gait Patterns in Rats following Neonatal Spinal Cord Transection

“…In order to generate stepping, the lumbar spinal cord circuitry must adapt to the loss of the primary neurotransmitters responsible for activating the locomotor generating circuitry. For example, recent evidence indicates remarkable changes in serotonergic receptor function after transection in adult rats such that these receptors can impact locomotion even in the absence of neurotransmitter (Murray et al, 2010) and a similar phenomenon may occur in noradrenergic receptors (Rank et al, 2011). Compensatory changes in neurotransmitter systems contained within the spinal circuitry likely also occur but this has only been demonstrated for the inhibitory neurotransmitter, GABA, in adult ST cats (Tillakaratne et al, 2002).…”

Neuromodulation of neurons and synapses

“…Indirect effects include presynaptic modulation that can lead to changes in action potential shape [2–4 •• ], and postsynaptic modulation that for example increases voltage-gated inward currents to enhance EPSPs [5–7 • ]. We will discuss these effects in detail in the next section.…”

“…These modifications depend on both translation [113 • ] and transcription [114 • ]. Similarly, disruption of aminergic modulation in spinalized animals drastically increases the sensitivity of spinal interneurons to modulators [115] and enables motor neurons to recover persistent Ca 2+ currents as amine receptors become constitutively active [6,7 • ]. …”

Modulation of Alpha 1 Adrenergic Receptors on Urinary Bladder in Rat Spinal Cord Injury Model

“…Three subtypes, α1a, α1b, and α1d, have been identified in various mammalian organs and have been characterized by either molecular or pharmacokinetic techniques [4-11]. It is well known that the three α1 AR subtypes expressed in the prostate play a major role in prostatic smooth muscle contraction [11].…”

“…Because all α1a AR subtypes are expressed in the bladder body, it is reasonable to assume that selective α1 AR antagonists may have on specific roles not only in the bladder neck but also in the bladder body [4-7]. However, the molecular characterization of the AR subtypes in the body of the urinary bladder is not well established.…”