Periaqueductal gray

Endorphins are found primarily in the limbic system, hypothalamus, and brainstem. Enkephalins and dynorphin (in smaller quantities) are found primarily in the periaqueductal gray matter (PAG) of the midbrain, the limbic system, and the hypothalamus. These endogenous substances mimic the effects of morphine and other opiate drugs at many points in the analgesic system, including in the dorsal horns of the spinal cord. 

Figure 8.2 The endogenous analgesic system. The three major components of the endogenous analgesic system include the periaqueductal gray matter in the midbrain nucleus raphe magnus in the medulla and pain inhibitory complex in the dorsal horns of the spinal cord. This system causes presynaptic inhibition of pain fibers entering the spinal cord. The binding of enkephalin to opioid receptors on the pain fibers prevents release of the neurotransmitter, substance P. As a result, the pain signal is terminated in the spinal cord and does not ascend to higher centers in the CNS.

Figure 4.2 Model of the network responsible for paradoxical sleep onset and maintenance Abbreviations DRN, dorsal raphe nucleus 5-HT, serotonin LC, locus coeruleus NA, noradrenaline LDT, laterodorsal tegmental nucleus Ach, acetylcholine Me, magnocellular reticular nucleus Gly glycine DPMe, deep mesencephalic reticular nucleus PAG, periaqueductal gray DPGi, dorsal paragigantocellular reticular nucleus PPT, pedunculopontine nucleus PRN, pontine reticular nucleus SLD, sublaterodorsal nucleus Glu, glutamate Pef/HLA perifornical/lateral hypothalamic area Hcrt, hypocretin (i.e. orexin).

In rats, lesions targeting presumptively wake-active dopaminergic neurons that extend dorsally from the VTA into the ventral periaqueductal gray have recently been shown to result in c. 20% reductions in wakefulness (Lu et al. 2006). Daytime sleepiness and SOREMs were reported in a non-human primate following systemic delivery of the dopamine neurotoxin MPTP (Daley et al. 1999), and this was subsequently confirmed in two additional animals (Daley... 

Lu J., Jhou T. C., Saper C. B. (2006). Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter. J. Neurosci. 26(1), 193-202. 

Legradi GA, Rand WM, Hitz S, Nillni EA, Jackson IMD and Lechan RM (1996). Opiate withdrawal increases ProTRH gene expression in the ventrolateral column of the midbrain periaqueductal gray. Brain Research, 729, 10-19. 

Opposite modulation of opiate withdrawal behaviors on microinfusion of a protein kinase A inhibitor versus activator into the locus coeruleus or periaqueductal gray. J Neurosci 1997 17 8520-8527. 

Weber, RJ. and Pert, A., The periaqueductal gray matter mediates opiate-induced im-munosuppresion, Science, 245, 188, 1989. 

Lysle, D.T., Hoffman, K.E., and Dykstra, L.A., Evidence for the involvement of the caudal region of the periaqueductal gray in a subset of morphine-induced alterations of immune status, J. Pharmacol. Exp. Ther., 277, 1533, 1996. 

Yaksh, T. L., Yeung, J. C., and Rudy, T. A., Systematic examination in the rat of brain sites sensitive to the direct application of morphine Observation of differential effects within the periaqueductal gray, Brain Res., 114, 83, 1976. 

The midbrain (mesencephalon) is the top of the brain stem. The dorsal midbrain is the tectum, which is involved in eye movements and reflexive reactions to sensory stimuli. The mesencephalic reticular formation projects upward to the forebrain and is involved in arousal and attention. The periaqueductal gray area surrounds the cerebral aqueduct, and integrates analgesic, defensive/aggressive, sexual, and autonomic responses. The red nucleus and substantia nigra are important structures in motor function. 

Clements JR, Beitz AJ, Fletcher TF, Mullett MA. (1985). Immunoc ochemical localization of serotonin in the rat periaqueductal gray a quantitative light and electron microscopic study. J Comp Neurol. 236 60-70. 

Clements JR, MadI JE, Johnson RL, Larson AA, Beitz AJ. (1987). Localization of glutamate, glutaminase, aspartate, and aspartate aminotransferase in the rat midbrain periaqueductal gray. Exp Brain Res. 67 594-602. 

Llewelyn MB, Azami B, Grant CM, Roberts MHJ. (1981). Analgesia following microinjection of nicotine into the periaqueductal gray matter (PAG). Neurosci Lett. 7 S277. 

Peng YB, Lin Q, Willis WD. (1996). Involvement of alpha-2 adrenoceptors in the periaqueductal gray-induced inhibition of dorsal horn cell activity in rats. J Pharmacol Exp Ther. 278 125-35. 

Rossi GC, Pasternak GW, Bodnar RJ. (1994). Mu and delta opioid synergy between the periaqueductal gray and the rostro-ventral medulla. Brain Res. 665 85-93. 

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