Involvement of ventromedial medulla "multimodal, multireceptive" neurons in opiate spinal descending control system: a single-unit study of the effect of morphine in the awake, freely moving rat

Abstract

In the present work, we have studied the effects of systemic morphine on the electrophysiological properties of ventromedial medulla (VMM) neurons in the awake, freely moving rat. By means of a chronically implanted single-unit recording device, a drug delivery catheter, and the use of controlled innocuous and noxious cutaneous stimuli, we were able to study precisely the spontaneous and evoked VMM neuronal activities. We have particularly focused our attention upon the VMM "multimodal, multireceptive" units, excited by non-noxious and noxious stimuli (VMM MULT ON), which we have already determined as the neuronal class potentially involved in nociceptive processes at VMM level. We found that morphine (3 mg/kg, i.v.) does not affect the spontaneous activity of these neurons whereas their responses to noxious heat are strongly attenuated (70%), over a prolonged period (about 2 hr) associated with an increase in the response latency. This action of morphine appears to be pharmacologically specific since it is dose dependent to some extent, and is reversed by 0.3 mg/kg of naloxone. In parallel with this pharmacological specificity, we have also demonstrated a preferential physiological effect since the response of the VMM MULT ON neurons to light touch application is not affected by morphine. This specificity is emphasized by the fact that morphine does not modify the activity of the other VMM neuronal groups such as the units unresponsive to any kind of peripheral stimuli, and does not reveal "new" neuronal classes such as those we have found in previous studies after barbiturate administration. The differential effect upon the noxious versus innocuous inputs of these units produced by the opiate reinforces their participation in nociceptive processing since similar effects have been reported in well-known nociceptive somatosensory structures such as the dorsal horn of the spinal cord. Furthermore, although the precise mechanisms of action have not yet been determined, the spinal projection of the VMM MULT ON neurons, previously demonstrated by our group, suggests their involvement in an opiate descending spinal control system of nociception. Although speculative, one can imagine either a direct facilitatory MULT ON spinal effect being attenuated by morphine (disfacilitation), or a morphine-induced disinhibition of inhibitory GABAergic neurons acting upon the MULT ON neurons.

Opioids Disrupt Pro-Nociceptive Modulation Mediated by Raphe Magnus

“…Since suppression of the phasic responses of RM cells to noxious stimulation accompanies withdrawal suppression, it is the suppression of phasic cellular responses that mediates RM antinociception. Our findings confirm results obtained from ON cells in awake rats and reported 20 years ago, and extend our understanding to include the responses of OFF cells to morphine in an unanesthetized preparation (Martin et al, 1992). Moreover, we propose a unified model that connects the activity recorded from RM cells in unanesthetized and anesthetized rodents alike to nociceptive reactions.…”

“…Tonic excitation of OFF cells and inhibition of ON cells in response to various opioids administered by different routes techniques are consistent, often replicated, findings in anesthetized rats (Toda, 1982;Heinricher and Rosenfeld, 1985;Barbaro et al, 1986;Fang et al, 1989;Heinricher et al, 1992Heinricher et al, , 1994Brink et al, 2006;Hellman et al, 2007). However, a single study in the unanesthetized rat did not observe any change in tonic ON cell activity in response to morphine as is observed in anesthetized rats (Martin et al, 1992). This singular study reported that in response to morphine, the tonic activity of ON-like cells did not change.…”

“…showed morphine had no effect on the spontaneous discharge of RM ON cells in awake rats (Martin et al, 1992). As Martin et al (1992) did not isolate or record from any OFF cells, their conclusions concerned ON cells exclusively.…”

“…As Martin et al (1992) did not isolate or record from any OFF cells, their conclusions concerned ON cells exclusively. A different group administered a high dose of morphine to unanesthetized rats and recorded the background discharge of RM units that were not characterized by their response to somatic stimulation (McGaraughty et al, 1993).…”

Serotonin immunoreactivity is contained in one physiological cell class in the rat rostral ventromedial medulla

“…Off cells increase their firing rate just prior to nociceptive withdrawal reflexes and become continuously active following systemic or supraspinal opioid administration. Although some investigators have not observed off cells in awake rats (Oliveras et al, 1990;Martin et al, 1992) recently McGaraughty et al (1993) have demonstrated characteristic off-cell responses to systemic morphine in awake rats. On cells exhibit responses opposite to those of off cells; they increase their firing rate in response to noxious stimuli and are inhibited by morphine administration.…”