The periaqueductal or "central" gray is a group of neurons that surrounds the aqueduct and is divided into four major zones: dorsomedial, dorsolateral, ventrolateral, and medial (Fig. 8). The medial portion immediately surrounds the aqueduct. Modulation of at least five primary behaviors has been attributed to portions of the periaqueductal gray: (1) modulation of pain pathways; (2) reproductive behavior (i.e., lordosis); (3) fear and anxiety; (4) vocalizations; and (5) autonomic regulation (i.e., control of blood pressure). The functions of the periaqueductal gray in reproduc tive behavior and vocalization have been demonstrated primarily in rats and cats and have not been investigated in humans. Moreover, studies have demonstrated coordinated responses between blood pressure, anxiety, and analgesia, which are mediated via competing columns of periaqueductal gray cells. As a consequence, the following discussion will be directed toward understanding three of the five primary physiologic functions: pain control, autonomic regulation (e.g., blood pressure, pulse, respiration, etc.), and the generation of fear and anxiety.
The role of the periaqueductal gray in gating pain information arising from the spinal cord has been known for at least 30 years. Electrical stimulation in the midbrain periaqueductal gray produced a level of anesthesia that was compatible with performing an exploratory laparotomy in a rat. Similar "endogenous'' analgesia has been demonstrated during such activities as environmental stress, long-distance running, or sexual activity. Analgesia may also be modulated by mood and circadian rhythms. How are these functions organized?
Most of the antinociceptive effects of midbrain periaqueductal gray stimulation can be mediated via connections to the nucleus raphe magnus located in the ventral rostral medulla. In turn, the nucleus raphe magnus provides afferents to the dorsal horn of the spinal cord via the dorsolateral funiculus. Two primary pathways target the nucleus raphe magnus. An opioid-dependent pathway, located in the ventrolat-eral portion of the midbrain periaqueductal gray has been confirmed using a variety of experimental techniques. Injection of morphine into the ventrolateral portion of the periaqueductal gray induces analgesia. Periaqueductal gray neurons are inhibited by enke-phalin, an endogenous opioid pentapeptide. The effects of stimulation in the ventrolateral portion of the periaqueductal gray (either by morphine or by electrical stimulation) can be reversed by the injection of Naloxone, an opioid antagonist. A second, non-opioid pain-modulating pathway arises from the dorsolateral portion of the periaqueductal gray. A similar level of analgesia can be generated by the injection of neurotensin or substance P, two peptide transmitters, into this region of the periaqueductal gray. The effects of these peptides and dorsolateral periaqueductal gray stimulation are not reversed by the injection of Naloxone, supporting the idea that the dorsolateral pathways are nonopioid-mediated. Some of these effects may also be modulated via ascending projections from the midbrain periaqueductal gray to the thalamus to cause a release of b-endorphin. The
thalamus may then reciprocally activate the midbrain periaqueductal gray. The periaqueductal gray also receives afferents from the prefrontal and insular cortices as well as the lateral and medial preoptic areas of the hypothalamus. The latter connections are much more important in the generation of lordosis behaviors than pain modulation. In sum, the primarily centrally acting, antinociceptive drugs provide much of their relief by activating opioid cells in the ventrolateral portion of the periaqueductal gray. Whereas there are a number of segmental and supraspinal descending antinociceptive systems, the periaqueductal gray provides the major descending control for both opioid and nonopioid-mediated analgesia.
Forebrain connections from the amygdala to the periaqueductal gray participate in the aversive responses of animals and in the fear and anxiety generated in humans from activation of dorsal regions of the periaqueductal gray. In addition, activation of the dorsolateral periaqueductal gray produces threat, associated with vocalization ("fight"), whereas activation of the caudal ventrolateral periaqueductal gray produces immobility or freezing effects ("flight"). These effects of stimulation (dorsolateral versus ven-trolateral) are also associated with changes in blood pressure and level of intrinsic nociception. The primary networks for maintaining the blood pressure and controlling respiration and heart rate are located in the medulla. The periaqueductal gray is part of an indirect path that regulates blood pressure in response to emotional state. The periaqueductal gray is interconnected with the lateral hypothalamic nucleus, periven-tricular nuclei, medial preoptic nucleus, amygdala, prefrontal cortex, and insular cortex. It also has projections to all of the medullary nuclei that participate in the regulation of blood pressure. Stimulation in the dorsolateral periaqueductal gray increased blood pressure, whereas activation of the ventrolateral periaqueductal gray produced hypotension.
This has led to the concept that a constellation of physiologic responses occurs following activation of these two different regions of the periaqueductal gray (Fig. 8). The fight response following dorsolateral activation is characterized by marked hypertension, increased blood flow to the face, decreased blood flow to the limbs and viscera, tachycardia, and nonopioid analgesia. Activation of the ventrolateral periaque-ductal gray is characterized by quiescence, hyporeac-tivity, hypotension, bradycardia, and opioid analgesia. The blood flow increases to the limbs but decreases to the viscera and face.
The ventrolateral and dorsolateral regions are probably mutually inhibitory, mediated by the action of intrinsic GABAergic interneurons. Injection of bicuculline (a blocker of GABA-A receptors) during stimulation of the dorsal periaqueductal gray blocked the anxiolytic (antianxiety) effect of injected diazepam. Two additional neurotransmitters participate in the pharmacology of anxiety and fear: 5-hydroxytrypto-phan (serotonin) and CCK (cholecystokinin). In humans 5HT1A (serotonin receptor subtype) agonists have been shown to be anxiolytic and this effect is probably mediated by inhibition of dorsal raphe neurons. Injections of CCK in human volunteers generated panic attacks. CCK also decreased the threshold to painful stimuli, whereas activation of the ventrolateral periaqueductal gray with enkephalin produced inhibition of nucleus raphe magnus projecting neurons.
Careful anatomic studies have further demonstrated that these two regions of the periaqueductal gray are organized in longitudinal rostral-caudal columns of cells with different afferent and efferent connections. The periaqueductal gray lateral, ventrolateral, and dorsomedial to the aqueduct project to the ventrome-dial and ventrolateral medulla. The dorsolateral periaqueductal gray, on the other hand, projects to the cuneiform nucleus and the periabducens regions of the rostral dorsomedial pons, but not the medulla. The dorsolateral periaqueductal gray column does not stain for cytochrome oxidase, but it has intense staining for acetylcholine-esterase or NADPH-dia-phorase. In addition, the labeling experiments have demonstrated that the lateral and ventrolateral portions of the periaqueductal gray have differential projections to the medulla. The ventrolateral portion ofthe periaqueductal gray projects to the periambigual region of the lateral medulla, which supplies vagal innervation to the heart. Ascending projections from the spinal cord and other brain stem regions have been shown to have topographic projections to the peria-queductal gray. In particular, precisely somatotopi-cally organized afferents arising from lumbar and cervical enlargements target the dorsolateral column of the periaqueductal gray. In contrast, the ventrolat-eral column is targeted by lumbar and cervical afferents but without any specific somatotopic arrangement. This correlates well with the observed differential behaviors of activating the dorsolateral (fight) versus ventrolateral (flight) portions of the periaqueductal gray.
Cortical inputs to the periaqueductal gray have differential projections to the dorsolateral and ven-trolateral cell columns. In the rat, descending cortico-fugal projections target restricted parts of the periaqueductal gray and terminate as one or two longitudinal columns along the rostrocaudal axis of the periaqueductal gray. Massive subcortical projections to the periaqueductal gray arise from the medial preoptic region and central nucleus of the amygdala and probably mediate many of the observed behavioral responses to periaqueductal gray stimulation. The medial preoptic region has been strongly implicated in neuroendocrine (gonadal steroid) regulation, sexual behavior, thermal regulation, and sleep. The projections of the medial preoptic region are primarily to the dorsomedial and dorsolateral columns of the peria-queductal gray at rostral levels. Further caudally the projection becomes distinctly bicolumnar with dense labeling in the dorsomedial and lateral cell columns. The central nucleus of the amygdala has been strongly implicated in the mediation of defensive behaviors and antinociception. Its projections at rostral levels to the periaqueductal gray are primarily confined to the medial periaqueductal gray. At the level of the oculomotor nuclei, the projection density increases markedly and forms dense dorsomedial and ventro-lateral input columns separated by the dorsolateral periaqueductal gray, which receives much less input from the central nucleus of the amygdala. Caudally the central nucleus of the amygdala projects primarily to the lateral and ventrolateral but to neither the dorsomedial nor the dorsolateral periaqueductal gray column. In conclusion, there is compelling evidence for three manifestations of the columnar organization of the periaqueductal gray: (1) discrete physiologic-behavioral functions (fight or flight responses); (2) differential projections from the dorsolateral and ventrolateral portions of the periaqueductal gray to the medulla; and (3) respect of specific, longitudinal columnar boundaries for the various inputs and outputs of the periaqueductal gray.
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