Synergistic Enhancement of Glutamate-Mediated Responses by Serotonin and Forskolin in Adult Mouse Spinal Dorsal Horn Neurons

Abstract

Wang, Guo-Du and Min Zhuo. Synergistic enhancement of glutamate-mediated responses by serotonin and forskolin in adult mouse spinal dorsal horn neurons. J Neurophysiol 87: 732-739, 2002; 10.1152/jn.00423.2001. Glutamate is the major excitatory amino acid neurotransmitter in the CNS, including the neocortex, hippocampus, and spinal cord. Normal synaptic transmission is mainly mediated by glutamate AMPA and/or kainate receptors. Glutamate N-methyl-Daspartate (NMDA) receptors are normally inactive and only activated when a sufficient postsynaptic depolarization is induced by the activity. Here we show that in sensory synapses of adult mouse, some synaptic responses (26.3% of a total of 38 experiments) between primary afferent fibers and dorsal horn neurons are almost completely mediated by NMDA receptors. Dorsal root stimulation did not elicit any detectable AMPA/kainate receptor-mediated responses in these synapses. Unlike young spinal cord, serotonin alone did not produce any long-lasting synaptic enhancement in adult spinal dorsal horn neurons. However, co-application of the adenylyl cyclase activator forskolin and serotonin (5-HT) produced long-lasting enhancement, including the recruitment of functional AMPA receptor-mediated responses. Calcium-sensitive, calmodulin-regulated adenylyl cyclases (AC1, AC8) are required for the enhancement. Furthermore the thresholds for generating action potential responses were decreased, and, in many cases, co-application of forskolin and 5-HT led to the generation of action potentials by previously subthreshold stimulation of primary afferent fibers in the presence of the NMDA receptor blocker 2-amino-5-phosphonovaleric acid. Our results suggest that pure NMDA synapses exist on sensory neurons in adult spinal cord and that they may contribute to functional sensory transmission. The synergistic recruitment of functional AMPA responses by 5-HT and forskolin provides a new cellular mechanism for glutamatergic synapses in mammalian spinal cord.

The Stimulatory Effect of Cannabinoids on Calcium Uptake Is Mediated by G_s GTP-Binding Proteins and cAMP Formation

“…Similar synergism has been seen before be-tween forskolin and the stimulatory effects of isoproterenol [17], prostaglandin E 2 [18], serotonin [19] and the cannabinoid agonist HU210 [7]. This synergistic effect may imply a real cooperation between the various cellular components, or may simply result from experimental limitation of background noise, and the requirement to augment the signal by forskolin, so that the effect of DALN on cAMP formation can be discerned.…”

Presynaptic and Postsynaptic Amplifications of Neuropathic Pain in the Anterior Cingulate Cortex

“…In addition to cortical region, AC1 is also likely involved in spinal cord plasticity. In previous studies, we have demonstrated that genetic deletion of AC1 inhibits spinal cord LTP induced by pairing training protocol and synaptic facilitation induced by coapplication of forskolin and serotonin (Wang and Zhuo, 2002;Wei et al, 2006). Considering the increasing evidence of spinal LTP and descending facilitation in chronic pain, it is conceivable that spinal AC1 mechanisms may also contribute to allodynia.…”

Central amplification and fibromyalgia: Disorder of pain processing

“…''ON'' cells facilitate pain perception, whereas ''OFF'' cells take part in descending inhibition of pain (Fields, 2006). In the dorsal horn, 5-HT 1A receptors reduced pronociceptive transmission by reducing responsiveness of neurons to glutamate (Lopez-Garcia, 1998), whereas 5-HT 2 receptors activated ''silent'' glutaminergic neurons (Li and Zhuo, 1998;Wang and Zhuo, 2002), probably through recruitment of postsynaptic AMPA receptors (Li et al, 1999). This neuronal activation is believed to contribute to the expanded field of mechanical hyperalgesia that is characteristic of central amplification.…”