Brainstem

Abstract: The location of neurons generating the rhythm of breathing in mammals is unknown. By microsection of the neonatal rat brainstem in vitro, a limited region of the ventral medulla (the pre-Botzinger Complex) that contains neurons essential for rhythmogenesis was identified. Rhythm generation was eliminated by removal of only this region. Medullary slices containing the pre-Botzinger Complex generated respiratory-related oscillations similar to those generated by the whole brainstem in vitro, and neurons with voltage-dependent pacemaker-like properties were identified in this region. Thus, the respiratory rhythm in the mammalian neonatal nervous system may result from a population of conditional bursting pacemaker neurons in the pre-Botzinger Complex.

Abstract: Thanks largely to the study of the brainstem nuclei that mediate stimulation analgesia, the involvement of the monoamines in the descending control of pain is now well established. The periaqueductal grey, the raphe nuclei (NRM and DRN) and the locus coeruleus are all key brainstem sites for the control of nociceptive transmission in the spinal cord. Although the initial emphasis was on 5-HT as the transmitter mediating this control at spinal levels, it is clear from more recent work that NA has an equally important part to play. How (or even if) the two amines differ in their roles and actions in analgesia is, however, still an open question. The small size and complexity of the brainstem areas from which analgesia may be elicited by electrical stimulation complicates the interpretation of the data. Stimulating currents may spread to surrounding regions mediating opposite effects to that of the main region stimulated. Opiates and GABA are clearly involved in descending control at both brainstem and spinal levels, although the relative roles of the different types of amino-acid and opiate receptors is still hotly debated. Despite the fact that the first report on stimulation analgesia appeared more than a quarter of a century ago in 1969, the precise connections and cord synaptology are still the basis of ongoing research. It is perhaps ironic, in an issue dedicated to new molecules and mechanisms, that those transmitters most involved in descending inhibition should be such old and familiar friends.

Abstract: The anatomy, physiology, and pharmacology of an intrinsic neural network that monitors and modulates the activity of pain-transmitting neurons is reviewed. This system can be activated by opiate administration or by electrical stimulation of discrete brainstem sites. Evidence is presented that its pain-suppressing action is mediated in part by endogenous opiatelike compounds (endorphins). This pain suppression system is organized at three levels of the neuraxis: midbrain, medulla, and spinal cord. Activation of neurons in the midbrain periaqueductal gray matter (by electrical stimulation, opiates, and possibly psychological factors) excites neurons of the rostral medulla, some of which contain serotonin. The medullary neurons, in turn, project to and specifically inhibit the firing of trigeminal and spinal pain-transmission neurons. As part of a negative feedback loop, the output of the pain transmission neurons, i.e., pain itself, is an important factor in activating the pain-suppression system. A neural model which incorporates the experimental findings is proposed, and the clinical implications of the model are discussed.

Abstract: C-fos is a proto-oncogene that is expressed within some neurons following depolarization. The protein product, c-fos protein, can be identified by immunohistochemical techniques. Therefore, c-fos expression might be used as a marker for neuronal activity throughout the neuraxis following peripheral stimulation. This study has analyzed patterns of c-fos expression in both control and anesthetized animals and in anesthetized rats subjected to various forms of peripheral stimulation. Labeled cells were counted in the spinal cord, brainstem, hypothalamus, and thalamus. Little c-fos immunoreactivity was found in control animals. Prolonged inhalational anesthesia increased the number of labeled cells at several brainstem sites. Noxious stimulation of anesthetized rats induced c-fos within the neuraxis in patterns consistent with data obtained from electrophysiological studies and in additional locations for which few direct electrophysiological data are available, such as the ventrolateral medulla, the posterior hypothalamic nucleus, and the reuniens and paraventricular thalamic nuclei. Gentle mechanical stimulation was ineffective in inducing c-fos-like protein. The data suggest that c-fos can be used as a transynaptic marker for neuronal activity following noxious stimulation. However, c-fos is expressed only in some kinds of neurons following peripheral stimulation, and it therefore may be an incomplete marker for nociresponsive activity. In addition, at least a few neurons express c-fos protein in the absence of noxious stimulation. Experiments analyzing c-fos expression must be designed with care, as both extraneous stimuli and anesthetic depth influence the results.