Tonic descending facilitation from the rostral ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive tolerance

Abstract

Many clinical case reports have suggested that sustained opioid exposure can elicit unexpected, paradoxical pain. Here, we explore the possibility that (1) opioid-induced pain results from tonic activation of descending pain facilitation arising in the rostral ventromedial medulla (RVM) and (2) the presence of such pain manifests behaviorally as antinociceptive tolerance. Rats implanted subcutaneously with pellets or osmotic minipumps delivering morphine displayed time-related tactile allodynia and thermal hyperalgesia (i. e., opioid-induced "pain"); placebo pellets or saline minipumps did not change thresholds. Opioid-induced pain was observed while morphine delivery continued and while the rats were not in withdrawal. RVM lidocaine, or bilateral lesions of the dorsolateral funiculus (DLF), did not change response thresholds in placebo-pelleted rats but blocked opioid-induced pain. The intrathecal morphine antinociceptive dose-response curve (DRC) in morphine-pelleted rats was displaced to the right of that in placebo-pelleted rats, indicating antinociceptive "tolerance." RVM lidocaine or bilateral DLF lesion did not alter the intrathecal morphine DRC in placebo-pelleted rats but blocked the rightward displacement seen in morphine-pelleted animals. The subcutaneous morphine antinociceptive DRC in morphine-pelleted rats was displaced to the right of that in placebo-pelleted rats; this right shift was blocked by RVM lidocaine. The data show that (1) opioids elicit pain through tonic activation of bulbospinal facilitation from the RVM, (2) increased pain decreases spinal opioid antinociceptive potency, and (3) blockade of pain restores antinociceptive potency, revealing no change in antinociceptive signal transduction. These studies offer a mechanism for paradoxical opioid-induced pain and allow the development of approaches by which the loss of analgesic activity of opioids might be inhibited.

Fig. 1.

Male Sprague Dawley rats were implanted subcutaneously with either two placebo or two morphine (75 mg each) pellets. The 7 d of constant exposure to morphine pellets resulted in tactile allodynia indicated by a significant (*p≤ 0.05; Student's t test; n = 10) decrease in paw withdrawal thresholds to probing with von Frey filaments (A). The bilateral microinjection of lidocaine (0.5 μl; 4% w/v) into the RVM on day 7 blocked tactile allodynia when given 30 min before testing in morphine-pelleted rats (n = 10) (A). Rats with placebo pellets demonstrated no significant (p > 0.05) difference in paw withdrawal thresholds to probing with von Frey filaments on day 7. The bilateral microinjection of lidocaine (0.5 μl; 4% w/v) into the RVM on day 7 produced no changes in paw withdrawal thresholds in placebo-pelleted rats (A). The exposure to subcutaneous morphine pellets also resulted in thermal hyperalgesia indicated by a significant (*p ≤ 0.05; Student'st test; n = 10) decrease in paw withdrawal latencies to radiant heat applied to the plantar aspect of the hindpaw (B). The bilateral microinjection of lidocaine (0.5 μl; 4% w/v) on day 7 blocked thermal hyperalgesia when given 30 min before testing in morphine-pelleted rats (n = 10) (B). Placebo-pelleted animals demonstrated no significant (p > 0.05) difference in paw withdrawal latencies to radiant heat on day 7, nor were there any significant changes after the bilateral RVM administration of lidocaine (0.5 μl; 4% w/v) (B).

Fig. 2.

Male Sprague Dawley rats received subcutaneous implantation of placebo or morphine pellets (two 75 mg pellets or 150 mg/animal). Paw withdrawal thresholds to probing with von Frey filaments (A) and paw withdrawal latencies to radiant heat (B) applied to the plantar aspect of the hindpaw were determined 2 and 6 hr after implantation and once daily afterward for 7 d. Morphine pellets initially produced antinociception (at 2 and 6 hr) in the radiant heat paw-flick test (B). Subsequently, tactile allodynia and thermal hyperalgesia, as indicated by a decrease in paw withdrawal thresholds and latencies were observed. Allodynia and hyperalgesia were significant (*p ≤ 0.05; Student'st test; n = 6) by the second day after morphine pellet implantation.

Fig. 3.

Male Sprague Dawley rats received either bilateral lesions of the DLF or sham lesions. In addition, 2 d after surgery, animals received either subcutaneous implantation of placebo pellets or morphine (75 mg) pellets. No significant differences were observed in paw withdrawal thresholds to probing with von Frey filaments or to paw withdrawal latencies to radiant heat between animals receiving sham surgery and placebo pellets or DLF ablation and placebo pellets (A). Morphine pellet implantation resulted in tactile allodynia, as indicated by a significant (*p ≤ 0.05; Student's t test;n = 10) decrease in paw withdrawal thresholds to probing with von Frey filaments (A), and thermal hyperalgesia, indicated by decreased paw withdrawal latencies to radiant heat (B), in the rats with sham DLF lesions. However, morphine-induced tactile allodynia (A) and thermal hyperalgesia (B) both were completely blocked in animals with bilateral DLF lesions. The paw withdrawal thresholds to probing with von Frey filaments and paw and the withdrawal latencies to radiant heat were significantly (†p ≤ 0.05; Student's t test; n = 10) greater than those of morphine-pelleted, sham-lesioned rats. C,A schematic of the cross-sectional view of the thoracic spinal cord. The shaded area depicts the area of bilateral DLF lesions.

Fig. 4.

Male Sprague Dawley rats were implanted subcutaneous with either two placebo or two morphine (75 mg each) pellets. Antinociceptive dose–response curves for intrathecal morphine were generated in the 52°C water tail flick test at the time of peak effect of morphine (30 min as determined by pilot experiments). One group each of rats with placebo pellets and with morphine pellets received morphine intrathecally concurrently with bilateral RVM lidocaine (0.5 μl; 4% w/v). The following groups were used: placebo-pelleted rats with bilateral RVM saline and challenged with intrathecal morphine (○), placebo-pelleted rats with bilateral RVM lidocaine and challenged with intrathecal morphine (■), morphine-pelleted rats with bilateral RVM saline and challenged with intrathecal morphine (●), and morphine-pelleted rats with bilateral RVM lidocaine and challenged with intrathecal morphine (▪). The dose–effect curve for intrathecal morphine in the morphine-pelleted group was shifted significantly to the right of that for the placebo-pelleted group. This dose–effect curve was restored that of the placebo-pelleted groups by RVM lidocaine.

Fig. 5.

Male Sprague Dawley rats were implanted subcutaneously with either two placebo or two morphine (75 mg each) pellets. Antinociceptive dose–response functions for intrathecal morphine were generated in the 52°C water tail flick test at the time of peak effect of morphine (30 min). Lidocaine (0.5 μl; 4% w/v) was microinjected into the RVM at 0, 10, and 20 min before and after intrathecal morphine. The A₅₀ values were lowest, and similar to placebo-implanted values, when lidocaine was given concurrently with morphine. The largestA₅₀ values occurred when lidocaine was given 20 min before or after intrathecal morphine. These results demonstrate the reversibility of the effect of RVM lidocaine and suggest a direct causal relationship between inhibition of RVM activity and loss of morphine antinociceptive tolerance.

Fig. 6.

Male Sprague Dawley rats received either bilateral lesions of the DLF or sham lesions. In addition, 2 d after surgery, animals received either subcutaneous implantation of placebo pellets or morphine (75 mg) pellets. After 7 d of pellet exposure, antinociceptive dose–response functions for intrathecal morphine were generated in the 52°C water tail flick test at the time of peak effect of morphine (30 min). The following groups were used: placebo-pelleted rats with sham DLF lesions (○), placebo-pelleted rats with DLF lesions (■), morphine-pelleted rats with sham DLF lesions (●), and morphine-pelleted rats with DLF lesions (▪). The dose–effect curve for intrathecal morphine in the morphine-pelleted group was shifted significantly to the right of that for the placebo-pelleted group. This dose–effect curve of the morphine-pelleted group with DLF lesions was not different from that of the placebo-pelleted groups.

Fig. 7.

Male Sprague Dawley rats were implanted subcutaneously with either two placebo or two morphine (75 mg each) pellets. Antinociceptive dose–response functions for subcutaneous morphine were generated in the 52°C water tail flick test at the time of peak effect of morphine (30 min). One group each of rats with placebo pellets and with morphine pellets received morphine subcutaneously concurrently with bilateral RVM lidocaine (0.5 μl; 4% w/v). The following groups were used: placebo-pelleted rats with bilateral RVM saline and challenged with subcutaneous morphine (○), placebo-pelleted rats with bilateral RVM lidocaine and challenged with subcutaneous morphine (■), morphine-pelleted rats with bilateral RVM saline and challenged with subcutaneous morphine (●), and morphine-pelleted rats with bilateral RVM lidocaine and challenged with subcutaneous morphine (▪). The dose–effect curve for subcutaneous morphine in the morphine-pelleted group was shifted significantly to the right of that for the placebo-pelleted group. This dose–effect curve was restored to that of the placebo-pelleted groups by RVM lidocaine.