Modulation of physiological reflexes by pain: role of the locus coeruleus

Abstract

The locus coeruleus (LC) is activated by noxious stimuli, and this activation leads to inhibition of perceived pain. As two physiological reflexes, the acoustic startle reflex and the pupillary light reflex, are sensitive to noxious stimuli, this review considers evidence that this sensitivity, at least to some extent, is mediated by the LC. The acoustic startle reflex, contraction of a large body of skeletal muscles in response to a sudden loud acoustic stimulus, can be enhanced by both directly (“sensitization”) and indirectly (“fear conditioning”) applied noxious stimuli. Fear-conditioning involves the association of a noxious (unconditioned) stimulus with a neutral (conditioned) stimulus (e.g., light), leading to the ability of the conditioned stimulus to evoke the “pain response”. The enhancement of the startle response by conditioned fear (“fear-potentiated startle”) involves the activation of the amygdala. The LC may also be involved in both sensitization and fear potentiation: pain signals activate the LC both directly and indirectly via the amygdala, which results in enhanced motoneurone activity, leading to an enhanced muscular response. Pupil diameter is under dual sympathetic/parasympathetic control, the sympathetic (noradrenergic) output dilating, and the parasympathetic (cholinergic) output constricting the pupil. The light reflex (constriction of the pupil in response to a light stimulus) operates via the parasympathetic output. The LC exerts a dual influence on pupillary control: it contributes to the sympathetic outflow and attenuates the parasympathetic output by inhibiting the Edinger-Westphal nucleus, the preganglionic cholinergic nucleus in the light reflex pathway. Noxious stimulation results in pupil dilation (“reflex dilation”), without any change in the light reflex response, consistent with sympathetic activation via the LC. Conditioned fear, on the other hand, results in the attenuation of the light reflex response (“fear-inhibited light reflex”), consistent with the inhibition of the parasympathetic light reflex via the LC. It is suggested that directly applied pain and fear-conditioning may affect different populations of autonomic neurones in the LC, directly applied pain activating sympathetic and fear-conditioning parasympathetic premotor neurones.

Orthopedic surgery modulates neuropeptides and BDNF expression at the spinal and hippocampal levels

“…An example of a possible pathway from the spinal cord to the forebrain relaying pain could include the paragigantocellular nucleus (38) and the noradrenergic locus coeruleus (39), which widely projects to forebrain areas, including the hippocampal formation (40). Noradrenergic mechanisms in pain modulation have been thoroughly explored (41,42).…”

Spontaneous pupil dilations during the resting state are associated with activation of the salience network

“…The LC features both an excitatory connection to the sympathetic innervation pathway of the pupil (originating in the intermediolateral cell column of the spinal cord) and an inhibitory connection to the parasympathetic pathway (originating in the midbrain Edinger-Westphal nucleus; Szabadi 2013). Consequently, increased LC activity involves increased sympathetic and decreased parasympathetic pupil innervation, causing a relative size increase (referred to as dilation) of the pupil (Szabadi 2012). During low vigilance levels, the mean pupil diameter is reduced (Henson and Emuh 2010;Ranzijn and Lack 1997), reflecting low tonic firing rates of LC neurons and a dominant parasympathetic innervation of the pupil.…”

Effects of vagus nerve stimulation on pupillary function

“…The LC is an important autonomic regulation center as it is the major noradrenergic nucleus (AstonJones et al, 1986). The LC can modulate both sympathetic and parasympathetic outflow to the pupil (Koss, 1986;Szabadi, 2012;Szabadi, 2013). The effect of VNS on resting pupil M A N U S C R I P T…”

“…The pupillary light reflex involves a direct and an indirect pathway: In the direct pathway, the light reaching the retina stimulates the olivary pretectal nucleus, then the EW nucleus and finally the CG. In the indirect pathway, two hypothalamic nuclei are stimulated, the suprachiasmatic nucleus and the ventrolateral preoptic nucleus, which are both connected to the LC nucleus (Klooster and Vrensen, 1998;Szabadi, 2012). Light also inhibits sympathetic activity through the paraventricular hypothalamus (Szabadi, 2012).…”