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. 2016 Dec;157(12):2697-2708.
doi: 10.1097/j.pain.0000000000000688.

Parabrachial Complex Links Pain Transmission to Descending Pain Modulation

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Free PMC article

Parabrachial Complex Links Pain Transmission to Descending Pain Modulation

Zachary Roeder et al. Pain. .
Free PMC article

Abstract

The rostral ventromedial medulla (RVM) has a well-documented role in pain modulation and exerts antinociceptive and pronociceptive influences mediated by 2 distinct classes of neurons, OFF-cells and ON-cells. OFF-cells are defined by a sudden pause in firing in response to nociceptive inputs, whereas ON-cells are characterized by a "burst" of activity. Although these reflex-related changes in ON- and OFF-cell firing are critical to their pain-modulating function, the pathways mediating these responses have not been identified. The present experiments were designed to test the hypothesis that nociceptive input to the RVM is relayed through the parabrachial complex (PB). In electrophysiological studies, ON- and OFF-cells were recorded in the RVM of lightly anesthetized male rats before and after an infusion of lidocaine or muscimol into PB. The ON-cell burst and OFF-cell pause evoked by noxious heat or mechanical probing were substantially attenuated by inactivation of the lateral, but not medial, parabrachial area. Retrograde tracing studies showed that neurons projecting to the RVM were scattered throughout PB. Few of these neurons expressed calcitonin gene-related peptide, suggesting that the RVM projection from PB is distinct from that to the amygdala. These data show that a substantial component of "bottom-up" nociceptive drive to RVM pain-modulating neurons is relayed through the PB. While the PB is well known as an important relay for ascending nociceptive information, its functional connection with the RVM allows the spinoparabrachial pathway to access descending control systems as part of a recurrent circuit.

Conflict of interest statement

The authors report no conflict of interest.

Figures

Fig. 1
Fig. 1
Locations of microinjection sites in the lateral PB complex and medial PB area. Injections were distributed among sections at +0.24 to −0.36 relative to the interaural line. KF: Kölliker-Fuse, lPB: lateral parabrachial complex, mPB: medial parabrachial area, scp: superior cerebellar peduncle.
Fig. 2
Fig. 2. Examples of the effect of lateral PB block on noxious stimulus-evoked, reflex-related activity of ON- and OFF-cells
Representative examples show OFF- and ON-cell activity during withdrawal from noxious heat stimulus at baseline compared to during lidocaine block of lateral PB contralateral to the stimulus, as well as subsequent recovery. In both cases, reflex-related changes in firing were substantially reduced, although not entirely eliminated. Increased spontaneous firing of the OFF-cell is also evident.
Fig. 3
Fig. 3. Inactivation of lateral PB interfered with the ON-cell burst and OFF-cell pause in response to heat stimulation
A. ON-cells. Effect of lateral PB microinjection of aCSF (200 nl), lidocaine (4%, 200 nl), or muscimol (8 pmol in 200 nl) on the ON-cell burst (measured as total evoked spikes). B. OFF-cells. Effect of lateral PB microinjection of aCSF, lidocaine, or muscimol on OFF-cell pause (measured as pause duration). (PB injections were contralateral to the peripheral stimulus. Reported as geometric mean with 95% confidence limits, *p < 0.05 compared to baseline, t-test for correlated means, n = 8 to 11 cells per class/treatment.)
Fig. 4
Fig. 4. Examples of the effect of lateral PB block on mechanically evoked, reflex-related activity of ON- and OFF-cells
Representative examples show ON- and OFF-cell activity and associated EMG during trials using 26, 60, and 100 g von Frey probes both in baseline and during PB block. A baseline (top-trace) and block trial (lower trace) are shown for each force. Reflex-related changes in firing were substantially reduced in both cases, and even eliminated for the ON-cell. Period of von Frey fiber application (8 s) is shown below each trace, with arrowhead indicating behavioral responses, which occurred in response to 60 and 100 g stimuli in baseline.
Fig. 5
Fig. 5. Inactivation of lateral PB interfered with the ON-cell burst and OFF-cell pause in response to mechanical stimulation
A. ON-cells. Effect of lidocaine (4%, 200 nl) microinjected into the lateral PB on activity triggered during application of von Frey probes (26, 60 and 100 g, measured as total evoked spikes, n = 8). B. OFF-cells. Effect of lidocaine (4%, 200 nl) microinjected into the lateral PB on OFF-cell pause (measured as pause duration, n = 13). (PB injections were contralateral to the peripheral stimulus. Reported as geometric mean with 95% confidence limits, t-test for correlated means, *p < 0.05, **p < 0.01 compared to baseline.) Statistical analysis. ON-cells (n = 8): 26 g: t7 = 3.80, p = 0.0067; 60 g: t5 = 6.99, p = 0.0009 (two cells active at stimulus onset; 100 g: t7 = 3.77, p = 0.0069. OFF-cells (n = 13): 26 g: t11 = 2.67, p = 0.022 (one cell silent at stimulus onset); 60 g: t11 = 3.17, p = 0.009 (one cell silent at stimulus onset); 100 g: t11 = 3.81, p = 0.0029 (one cell silent at stimulus onset).
Fig. 6
Fig. 6. The latencies of the residual ON-cell burst and OFF-cell pause were increased during inactivation of lateral PB
Effect of lateral PB block (lidocaine) on the latencies of the ON-cell burst and OFF-cell pause during noxious heat (A) and stimulation with VF probes (26, 60 and 100 g, B and C). (PB injections were contralateral to the peripheral stimulus. Mean + SEM, *p < 0.05, **p < 0.01 compared to baseline using t-test for correlated means or Wilcoxon’s signed ranks test, 8 to 13 cells/group) Statistical analysis: Heat. Pause: t10 = 3.93, p = 0.0028, n = 11, Burst: t10 = 3.84, p = 0.0033, n = 11. Mechanical stimulation, pause. 26 g: W = 11, p = 0.19, n = 13; 60 g: W = 78, p = 0.0005, n = 13 (with one cell silent); 100 g: W = 74, p = 0.0015, n = 13 (with one cell silent). Mechanical stimulation, burst. 26 g: W = 10, p = 0.12, n = 8; 60 g: W = 21, p = 0.031, n = 8 (two cells active); 100 g: W = 24, p = 0.047, n = 8.
Fig. 7
Fig. 7. Modest behavioral hypoalgesia during inactivation of lateral PB
A. Effect of lidocaine or aCSF microinjected into the lateral PB on latency to heat-evoked withdrawal. Latency was significantly increased during lidocaine block of PB (t25 = 2.17, p = 0.040, n = 26), but unaffected by injection of aCSF (t14 = 0.43, p = 0.68, n = 15). B. Effect of lidocaine microinjected into the lateral PB on withdrawal evoked by VF probes (26, 60 and 100 g, n = 22, number of animals not responding within 8 s cut-off time shown within each bar). Latency was increased for stimuli in the noxious range (60 g: W = 243, p < 0.0001, n = 22; 100 g: W = 203, p = 0.0004, n = 22) but not for the 26 g stimulus (W = 31, p = 0.13, n = 22). PB injections were contralateral to the peripheral stimulus. (Data shown as mean + SEM, *p < 0.05, **p < 0.01 compared to baseline using t-test for correlated means or Wilcoxon’s signed ranks test.)
Fig. 8
Fig. 8. Effect of lidocaine (4%, 200 nl) microinjected into the lateral PB on spontaneous firing of OFF-cells, ON-cells, and NEUTRAL-cells in RVM
OFF-cell firing was significantly increased (t12 = 3.77, p = 0.0027, n = 13), while ON-cell firing was reduced (t7 = 3.03, p = 0.0019, n = 8). NEUTRAL-cells did not respond to lateral PB block (t5 = 0.98, p = 0.37, n = 6). (PB injection was unilateral. Geometric mean with 95% confidence limits, *p < 0.05, **p < 0.01 compared to pre-block baseline using t-test for correlated means)
Fig. 9
Fig. 9. Medial PB (mPB) does not contribute to the ON-cell burst and OFF-cell pause
A. Muscimol (8 pmol in 200 nl) microinjected into the mPB and adjacent tegmentum had no effect on heat-evoked activity of ON-cells (t7 = 1.26, p = 0.25, n = 8). B. Muscimol (8 pmol in 200 nl) microinjected into the mPB and adjacent tegmentum had no effect on the heat-related OFF-cell pause (t5 = 1.34, p = 0.24, n = 7 with one neuron silent at heat onset). (PB injections were contralateral to the peripheral stimulus. Reported as geometric mean with 95% confidence limits.)
Fig. 10
Fig. 10. CGRP-ir neurons in PB do not project to the RVM
A Schematic representation of the PB. Immunohistochemical label for FG (B, green), CGRP (C, red) and overlap (D) in the PB. Da. Inset showing higher magnification view of the only CGRP/FG double labeled neuron found in PB. Db. Inset showing higher magnification view illustrates segregation of CGRP-ir neurons from RVM-projecting neurons.

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