Circuitry linking opioid-sensitive nociceptive modulatory systems in periaqueductal gray and spinal cord with rostral ventromedial medulla

doi:10.1016/0306-4522(92)90036-2

Neuroscience

Volume 47, Issue 4, April 1992, Pages 863-871

https://doi.org/10.1016/0306-4522(92)90036-2 Get rights and content

Abstract

The interactions among opioid-sensitive nociceptive modulatory systems, which include the midbrain periaqueductal gray, rostral ventromedial medulla and spinal cord, are likely to play a central role in the potent antinociception that results when morphine is administered systemically. The aim of the present study was to investigate the mechanisms through which local application of morphine, either in the periaqueductal gray or at the lumbar spinal cord in the rat, influences the activity of one population of putative nociceptive modulatory neurons in rostral ventromedial medulla, i.e. “on-cells”. Previous studies have shown that the spontaneous and tail-flick-related firing of on-cells is invariably depressed when morphine is given systemically in doses demonstrated to inhibit the tail-flick reflex, and that a similar depression of this activity is produced when morphine is applied directly in the periaqueductal gray or intrathecal space. In the present experiments, on-cells were activated pharmacologically using iontophoretically applied glutamate to provide an indication of whether morphine-induced suppression of on-cell firing reflected a postsynaptic inhibition or a disfacilitation resulting from blockade of an excitatory input to the on-cell.

Microinjection of morphine into the periaqueductal gray blocked glutamate-evoked activity of on-cells in parallel with its suppression of the tail-flick reflex, suggesting activation of an inhibitory input to these cells. No change in glutamate-evoked activity occurred in rats in which morphine did not produce antinociception. Intrathecal administration of morphine did not alter the glutamate-evoked activity of these neurons despite blocking the tail-flick reflex, suggesting that morphine acting in the spinal cord removes an excitatory input to on-cells.

Thus, in addition to possible direct effects of morphine on rostral ventromedial medulla on-cells, morphine administered systemically will simultaneously engage inhibitory influences from the periaqueductal gray and remove facilitating inputs from the spinal cord. Each of these mechanisms is likely to contribute to the potent antinociception that results when morphine is administered systemically.

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Other functions have also been proposed (Mason, 2001). Experimental evidence indicates that on-cells contribute to inflammation-, neuropathy- and stress-induced hyperalgesia and allodynia (Carlson et al., 2007; Cleary and Heinricher, 2013; Edelmayer et al., 2009; Goncalves et al., 2007; Khasabov et al., 2012; Martenson et al., 2009; Porreca et al., 2001; Zhang et al., 2009) while off-cells mediate descending inhibition of nociception by opioids, cannabinoids and nonsteroidal anti-inflammatory drugs (Barbaro et al., 1986; Fields et al., 1983b; Fields, 2004; Harasawa et al., 2000; Heinricher et al., 1992; Heinricher et al., 1994; Meng et al., 1998; Morgan et al., 1992; Pan and Fields, 1996; Tortorici and Vanegas, 1994, 1995; Tortorici et al., 2001). Both on- and off-cells project to the spinal cord (Vanegas et al., 1984), their axons terminate in the dorsal horn (Fields et al., 1995) and their influences upon nociception are supposed to be mediated by spinal mechanisms that modify the excitability of the spinal nociceptive neurons involved in withdrawal reflexes and in the ascending nociceptive information that eventually reaches the cerebral cortex.
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