Effects of general anesthetics on visceral pain transmission in the spinal cord

Abstract

Current evidence suggests an analgesic role for the spinal cord action of general anesthetics; however, the cellular population and intracellular mechanisms underlying anti-visceral pain by general anesthetics still remain unclear. It is known that visceral nociceptive signals are transmited via post-synaptic dorsal column (PSDC) and spinothalamic tract (STT) neuronal pathways and that the PSDC pathway plays a major role in visceral nociception. Animal studies report that persistent changes including nociception-associated molecular expression (e.g. neurokinin-1 (NK-1) receptors) and activation of signal transduction cascades (such as the protein kinase A [PKA]-c-AMP-responsive element binding [CREB] cascade)-in spinal PSDC neurons are observed following visceral pain stimulation. The clinical practice of interruption of the spinal PSDC pathway in patients with cancer pain further supports a role of this group of neurons in the development and maintenance of visceral pain. We propose the hypothesis that general anesthetics might affect critical molecular targets such as NK-1 and glutamate receptors, as well as intracellular signaling by CaM kinase II, protein kinase C (PKC), PKA, and MAP kinase cascades in PSDC neurons, which contribute to the neurotransmission of visceral pain signaling. This would help elucidate the mechanism of antivisceral nociception by general anesthetics at the cellular and molecular levels and aid in development of novel therapeutic strategies to improve clinical management of visceral pain.

Figure 1

Dorsal column pathway of visceral pain transmission. Adapted from Nauta HJ, et al. Surgical interruption of a midline dorsal column visceral pain pathway. J Neurosurg, 86:538–542, 1997. The dorsal column pathway is composed of branches of primary afferent fibers, some of which project directly to the dorsal column nuclei, and of the axons of postsynaptic dorsal column neurons. Pelvic viscera nociceptive input activates the postsynaptic dorsal column neurons of the spinal cord and is relayed to higher centers. PSDC neurons receiving pelvic visceral input send their axons in the midline of the dorsal column to synapse in the nucleus gracilis. Then, the pathway crosses the midline in the lower brainstem to ascend to the ventral posterolateral nucleus of the thalamus. PSDC (postsynaptic dorsal column); VPL (ventral posterolateral), DRG (dorsal root ganglion).

Figure 2

Neurochemical signal transduction pathways in the PSDC neurons in response to visceral stimuli. The activation of nociceptive receptors causes a large influx of calcium into the nociceptive neurons and the increased calcium influx, in turn, activates multiple intracellular protein kinases. PKA regulates the phosphorylation of glutamate receptors. Another important role for the activation of PKA in PSDC neurons is its effect on painful stimulation-elicited gene expression through mediation of transcription factors, such as c-fos and CREB. PKA in PSDC neurons might increase the expression of NK1 receptors through mediation of CREB and contribute to the sensitization of PSDC neurons.