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.

Keywords: acoustic startle reflex; fear-conditioning; locus coeruleus; pain; pupillary light reflex.

Figure 1

Central position of the locus coeruleus in relation to the acoustic startle reflex and pupillary light reflex pathways. Red: excitatory connections; blue: inhibitory connections. The acoustic startle response is triggered by a sound stimulus activating auditory receptors in the cochlea. Auditory signals are transmitted via two nuclei of auditory processing, the ventral cochlear nucleus and ventral nucleus of the lateral lemniscus, to a relay nucleus in the pontine reticular formation, nucleus reticularis pontis caudalis, which projects directly to bulbar and spinal motoneurones. The startle response consists of the sudden synchronized contraction of a large array of facial and skeletal muscles. The locus coeruleus has a facilitatory influence on the motor neurones via an excitatory noradrenergic output involving the stimulation of α₁-adrenoceptors. Painful stimuli, via activation of the locus coeruleus can enhance the acoustic startle response (“sensitization”). The reflex response can also be enhanced by fear-conditioning via the amygdala. The lateral nucleus of the amygdala processes the association between aversive (painful) unconditioned (UCS) stimuli and neutral (e.g., light) conditioned (CS) stimuli, and the arising conditioned fear signal is transmitted, via the central nucleus of the amygdala, to the nucleus reticularis pontis caudalis, leading to the enhancement of the reflex response (“fear-potentiation”). The amygdala also projects to the locus coeruleus, whose activation by conditioned fear contributes to the fear-potentiation of the acoustic startle response. The pupillary light reflex is a parasympathetic autonomic reflex. Light signals stimulate photoreceptors in the retina which project, via melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), to the pretectal nucleus, a parasympathetic premotor nucleus: this leads to activation of the reflex pathway via the chain Edinger Westphal nucleus (preganglionic neurones) → ciliary ganglion (postganlionic neurones). The reflex response is the contraction of the smooth muscle fibres of the sphincter pupillae muscle, leading to pupil constriction (miosis). The locus coeruleus has inhibitory influence on the preganglionic neurones via a noradrenergic projection involving α₂-adrenoceptors. As the locus coeruleus can be activated by the amygdala, it transmits conditioned fear signals to the Edinger Westphal nucleus, leading to the attenuation of the light reflex response by conditioned fear (“fear-inhibition”).

Figure 2

Neuronal network mediating the effect of light on pupil diameter. Red: excitatory connections, blue: inhibitory connections. Hypothalamic nuclei: SCN, suprachiasmatic nucleus; PVN, paraventricular nucleus; DMH, dorsomedial hypothalamus; autonomic premotor nuclei: OPN, olivary pretectal nucleus; LC, locus coeruleus; parasympathetic nucleus/ganglion: EW, Edinger Westphal nucleus; GC, ganglion ciliare; sympathetic nucleus/ganglion: IML, intermedio-lateral column of spinal cord; SCG, superior cervical ganglion. Neurotransmitters: Glu, glutamate; GABA, γ-amino-butyric acid; VP, vasopressin; Ox, orexin; ACh, acetylcholine; NA, noradrenaline. Adrenoceptors: α₁, excitatory and α₂, inhibitory. Pupil diameter reflects the relationship between two opposing smooth muscles, the dilator pupillae, innervated by the sympathetic, and sphincter (constrictor) pupillae (innervated by the parasympathetic). The locus coeruleus functions as both a sympathetic and a parasympathetic premotor nucleus: it stimulates preganglionic sympathetic neurones in the IML and inhibits preganglionic parasympathetic neurones in the EW. The pupillary light reflex is a parasympathetic reflex: light signals from the retina stimulate the chain OPN → EW → GC, leading to pupil constriction. Light also has an indirect effect on sympathetic activity via the SCN: sympathetic activity is inhibited via an inhibitory output to the PVN. Light-evoked sympatho-inhibition, however, is likely to be attenuated by sympatho-excitation mediatied via the SCN → DMH → LC route.

Figure 3

Neuronal network mediating the dual effect of light on arousal. Nuclei: yellow: wakefulness-promoting, purple: sleep-promoting. Connections: red: excitatory, blue: inhibitory. Hypothalamic nuclei: SCN, suprachiasmatic nucleus; DMH, dorso-medial hypothalamus; LH, lateral hypothalamic area; VLPO, ventrolateral preoptic nucleus; TMN, tuberomamillary nucleus; brainstem nucleus: LC, locus coeruleus. Neurotransmiters: Glu, glutamate; Ox, orexin; NA, noradenaline; H, histamine. Light reaching the retina has a sleep-promoting effect via the excitatory output of melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) to the VLPO, the major sleep-promoting nucleus. GABAergic inhibitory neurones in the VLPO project to the cerebral cortex, and two major wakefulness-promoting nuclei, the TMN and LC. Light also evokes a wakefulness-promoting effect via the SCN which can stimulate orexinergic and glutamatergic neurones in the DMH that project to two wakefulness-promoting nuclei, the LC and LH. There is a reciprocal inhibitory connection between the LC and the VLPO: GABAergic neurones in the VLPO inhibit the LC, and noradrenergic neurones in the LC inhibit the VLPO via the stimulation of α₂-adrenoceptors. The LC also stimulates the cortex and the TMN via excitatory outputs involving α₁-adrenoceptors. The orexinergic neurones of the LH send excitatory outputs to the LC and the cerebral cortex. The overall effect of light on arousal depends on the relationship between the two light-sensitive arousal systems. In nocturnal animals light is sleep-promoting due to the predominant effect of the activation of the VLPO by light. In diurnal animals, on the other hand, the sleep-promoting effect of VLPO activation by light, is likely to be superseded by the wakefulness-promoting influence of the activation of the LC and LH via the SCN → DMH → LC/LH route.