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Comments on Thurston and Randich
396 PAIN 2998
Comments on Thurston and Randich We are writing to comment on the conclusions of a recent paper by Thurston and Randich (1995). Their experiments studied correlations among the activity of On- and Off-cells in the rostral ventromedial medulla (RVM), changes in mean arterial blood pressure and nociception. Despite the paucity of data presented on nocifensor behaviors, one of their stated conclusions is that the role of On- and Off-cells in nociceptive modulation is not firmly established. In an elaboration of that conclusion, the authors state in their summary that their data indicate that On-cell excitation and Off-cell inhibition may inhibit nociception. This conclusion is evidently based on (1) the stated correlations between On- and Off-cell firing and fluctuations in blood pressure, and (2) the effects of electrical stimulation of the vagus nerve on On- and Off-cell activity at current intensities that also inhibit the tail flick. We disagree with their conclusion. First of all, even if it were established that activity in RVM On- a n d / o r Off-cells is causally related to associated changes in arterial pressure (a conclusion which even they agree is not established by their weak correlative data, p. 36, paragraph 5, lines 6-7), this would not necessarily contradict the idea that these neurons have a major function in modulating pain transmission. For example, activation of primary afferent nociceptors can result in changes in blood pressure, but this observation in no way detracts from the well-accepted major role of these afferents in nociception. Second, circuits independent of the RVM can modulate nociception. Such circuits would permit facilitatory or inhibitory modulation of nocifensor reflexes independent of activity in either RVM cell class. In such cases, the correlation of activity in a given RVM cell class with antinociception would have no necessary relation to the effect of that cell class on nociception. Thus, although Thurston and Randich (1992) previously showed that antinociception produced by electrical stimulation of the vagus correlates with suppression of Off-cell firing and activation of On-cells, this does not disprove the idea that activation of Off-cells exerts a net antinociceptive effect because the effect might involve circuits other than those of the RVM. Third, in a related point, there are at least three physiologically distinct cell classes in RVM. Thus, even though lesion experiments suggest that RVM neurons may be involved in this vagally mediated antinociception (Randich et al. 1990), lesions remove all cell populations within the RVM including neutral cells. Since neutral cells rather than On- or Off-cells could in principle be the major contributor to VAS-induced antinociception, the issue of whether RVM Ona n d / o r Off-cells contribute to VAS antinociception remains clouded. Fourth, under the conditions of the Thurston and Randich experiments, activation of some cell population within RVM clearly contributes to opioid inhibition of nocifensor reflexes, since lesions of the RVM attenuate the antinociceptive effect of systemically administered morphine (Randich et al. 1992). In their experiments Off-cells, but not On-cells, are activated by systemically administered morphine, thus their own results are more consistent with the idea that Off-cells inhibit nociception, than with their stated conclusion that it is inhibition, rather than activation, of Off-cells that inhibits nociception. Finally, the critical experiments bearing on the role of RVM Onand Off-cells are those in which the effect on nociceptive transmission of the relevant independent variables (RVM On- and Off-cell activity) can be isolated. When such experiments have been done, the conclusions are straightforward: activity in RVM Off-cells inhibits the tail-flick reflex, while activity in RVM On-cells enhances it. The clearest evidence on this point comes from direct local application of GABA antagonists or opioids into RVM, recording On- or
Off-cells in the region affected by the drug application, and measuring the effects on tail-flick latency. In these experiments low doses of bicuculline in RVM increase in Off-cell discharge, depress On-firing and inhibit the tail flick (Heinricher and Tortorici 1994). Furthermore, there is a close temporal correlation of the electrophysiology and behavior. Similarly, RVM nanoinjection of opioids produces a tail-flick inhibition that is associated with increased activity in Offcells and reduced activity in On-cells (Heinricher et al. 1994). It is worth noting in this context that the activity of RVM neutral cells is unaffected by opioids given systemically, into the PAG or applied directly by iontophoresis. Thus, with direct manipulation of the circuitry within the RVM, an increase in RVM Off-cell activity together with a decrease in On-cell activity is sufficient to inhibit the tail flick. In sum, work already published clearly satisfies the Thurston and Randich requirement that " . . . cause and effect relationships between ON and OFF cell activity and nociception ... must be determined before the role of ON and OFF cells in the modulation of nociception ... can be firmly established." (p. 37, last paragraph). The issue of the role of these neurons in cardiovascular control does, however, remain an open question. To date, there is no direct evidence that either On- or Off-cells have any effect on arterial pressure.
References Heinricher, M.M., Morgan, M.M., Tortorici, V. and Fields, H.L., Disinhibition of off-cells and antinociception produced by an opioid action within the rostral ventromedial medulla, Neuroscience, 63 (1994) 279-288. Heinricher, M.M. and Tortorici, V., Interference with GABA transmission in the rostral ventromedial medulla: disinhibition of off-cells as a central mechanism of nociceptive modulation, Neuroscience, 63 (1994) 533-546. Randich, A., Ren, K. and Gebhart, G.F., Electrical stimulation of cervical vagal afferents. II. Central relays for behavioral antinociception and arterial blood pressure decreases, J. Neurophysiol, 64 (1990) 1115-1124. Randich, A., Thurston, C.L., Ludwig, P.S., Robertson, J.D. and Rasmussen, C., Intravenous morphine-induced activation of vagal afferents: peripheral, spinal, and CNS substrates mediating inhibition of spinal nociception and cardiovascular responses, J. Neurophysiol, 68 (1992) 1027-1045. Thurston, C.L. and Randich, A., Effects of vagal afferent stimulation on ON and OFF cells in the rostroventral medulla: relationships to nociception and arterial blood pressure, J. Neurophysiol, 67 (1992) 180-196. Thurston, C.L. and Randich, A., Responses of on and off cells in the rostral ventral medulla to stimulation of vagal afferents and changes in mean arterial blood pressure in intact and cardiopulmonary deafferented rats, Pain, 62 (1995) 19-38.
Howard L. Fields Departments of Neurology and Physiology University of California San Francisco, CA 94143 (USA)
Mary M. Heinricher Oregon Health Sciences University Division of Neurosurgery (L472) Portland, OR 97201 (USA)
SSDI 0 3 0 4 - 3 9 5 9 ( 9 5 ) 0 0 2 0 9 - X
Comments on Thurston and Randich We are writing to comment on the conclusions of a recent paper by Thurston and Randich (1995). Their experiments studied correlations among the activity of On- and Off-cells in the rostral ventromedial medulla (RVM), changes in mean arterial blood pressure and nociception. Despite the paucity of data presented on nocifensor behaviors, one of their stated conclusions is that the role of On- and Off-cells in nociceptive modulation is not firmly established. In an elaboration of that conclusion, the authors state in their summary that their data indicate that On-cell excitation and Off-cell inhibition may inhibit nociception. This conclusion is evidently based on (1) the stated correlations between On- and Off-cell firing and fluctuations in blood pressure, and (2) the effects of electrical stimulation of the vagus nerve on On- and Off-cell activity at current intensities that also inhibit the tail flick. We disagree with their conclusion. First of all, even if it were established that activity in RVM On- a n d / o r Off-cells is causally related to associated changes in arterial pressure (a conclusion which even they agree is not established by their weak correlative data, p. 36, paragraph 5, lines 6-7), this would not necessarily contradict the idea that these neurons have a major function in modulating pain transmission. For example, activation of primary afferent nociceptors can result in changes in blood pressure, but this observation in no way detracts from the well-accepted major role of these afferents in nociception. Second, circuits independent of the RVM can modulate nociception. Such circuits would permit facilitatory or inhibitory modulation of nocifensor reflexes independent of activity in either RVM cell class. In such cases, the correlation of activity in a given RVM cell class with antinociception would have no necessary relation to the effect of that cell class on nociception. Thus, although Thurston and Randich (1992) previously showed that antinociception produced by electrical stimulation of the vagus correlates with suppression of Off-cell firing and activation of On-cells, this does not disprove the idea that activation of Off-cells exerts a net antinociceptive effect because the effect might involve circuits other than those of the RVM. Third, in a related point, there are at least three physiologically distinct cell classes in RVM. Thus, even though lesion experiments suggest that RVM neurons may be involved in this vagally mediated antinociception (Randich et al. 1990), lesions remove all cell populations within the RVM including neutral cells. Since neutral cells rather than On- or Off-cells could in principle be the major contributor to VAS-induced antinociception, the issue of whether RVM Ona n d / o r Off-cells contribute to VAS antinociception remains clouded. Fourth, under the conditions of the Thurston and Randich experiments, activation of some cell population within RVM clearly contributes to opioid inhibition of nocifensor reflexes, since lesions of the RVM attenuate the antinociceptive effect of systemically administered morphine (Randich et al. 1992). In their experiments Off-cells, but not On-cells, are activated by systemically administered morphine, thus their own results are more consistent with the idea that Off-cells inhibit nociception, than with their stated conclusion that it is inhibition, rather than activation, of Off-cells that inhibits nociception. Finally, the critical experiments bearing on the role of RVM Onand Off-cells are those in which the effect on nociceptive transmission of the relevant independent variables (RVM On- and Off-cell activity) can be isolated. When such experiments have been done, the conclusions are straightforward: activity in RVM Off-cells inhibits the tail-flick reflex, while activity in RVM On-cells enhances it. The clearest evidence on this point comes from direct local application of GABA antagonists or opioids into RVM, recording On- or
Off-cells in the region affected by the drug application, and measuring the effects on tail-flick latency. In these experiments low doses of bicuculline in RVM increase in Off-cell discharge, depress On-firing and inhibit the tail flick (Heinricher and Tortorici 1994). Furthermore, there is a close temporal correlation of the electrophysiology and behavior. Similarly, RVM nanoinjection of opioids produces a tail-flick inhibition that is associated with increased activity in Offcells and reduced activity in On-cells (Heinricher et al. 1994). It is worth noting in this context that the activity of RVM neutral cells is unaffected by opioids given systemically, into the PAG or applied directly by iontophoresis. Thus, with direct manipulation of the circuitry within the RVM, an increase in RVM Off-cell activity together with a decrease in On-cell activity is sufficient to inhibit the tail flick. In sum, work already published clearly satisfies the Thurston and Randich requirement that " . . . cause and effect relationships between ON and OFF cell activity and nociception ... must be determined before the role of ON and OFF cells in the modulation of nociception ... can be firmly established." (p. 37, last paragraph). The issue of the role of these neurons in cardiovascular control does, however, remain an open question. To date, there is no direct evidence that either On- or Off-cells have any effect on arterial pressure.
References Heinricher, M.M., Morgan, M.M., Tortorici, V. and Fields, H.L., Disinhibition of off-cells and antinociception produced by an opioid action within the rostral ventromedial medulla, Neuroscience, 63 (1994) 279-288. Heinricher, M.M. and Tortorici, V., Interference with GABA transmission in the rostral ventromedial medulla: disinhibition of off-cells as a central mechanism of nociceptive modulation, Neuroscience, 63 (1994) 533-546. Randich, A., Ren, K. and Gebhart, G.F., Electrical stimulation of cervical vagal afferents. II. Central relays for behavioral antinociception and arterial blood pressure decreases, J. Neurophysiol, 64 (1990) 1115-1124. Randich, A., Thurston, C.L., Ludwig, P.S., Robertson, J.D. and Rasmussen, C., Intravenous morphine-induced activation of vagal afferents: peripheral, spinal, and CNS substrates mediating inhibition of spinal nociception and cardiovascular responses, J. Neurophysiol, 68 (1992) 1027-1045. Thurston, C.L. and Randich, A., Effects of vagal afferent stimulation on ON and OFF cells in the rostroventral medulla: relationships to nociception and arterial blood pressure, J. Neurophysiol, 67 (1992) 180-196. Thurston, C.L. and Randich, A., Responses of on and off cells in the rostral ventral medulla to stimulation of vagal afferents and changes in mean arterial blood pressure in intact and cardiopulmonary deafferented rats, Pain, 62 (1995) 19-38.
Howard L. Fields Departments of Neurology and Physiology University of California San Francisco, CA 94143 (USA)
Mary M. Heinricher Oregon Health Sciences University Division of Neurosurgery (L472) Portland, OR 97201 (USA)
SSDI 0 3 0 4 - 3 9 5 9 ( 9 5 ) 0 0 2 0 9 - X