Time-dependent descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain

Abstract

Although injury-induced afferent discharge declines significantly over time, experimental neuropathic pain persists unchanged for long periods. These observations suggest that processes that initiate experimental neuropathic pain may differ from those that maintain such pain. Here, the role of descending facilitation arising from developing plasticity in the rostral ventromedial medulla (RVM) in the initiation and maintenance of experimental neuropathic pain was explored. Tactile and thermal hypersensitivity were induced in rats by spinal nerve ligation (SNL). RVM lidocaine blocked SNL-induced tactile and thermal hypersensitivity on post-SNL days 6-12 but not on post-SNL day 3. Lesion of RVM cells expressing mu-opioid receptors with dermorphin-saporin did not prevent the onset of SNL-induced tactile and thermal hypersensitivity, but these signs reversed to baseline levels beginning on post-SNL day 4. Similarly, lesions of the dorsolateral funiculus (DLF) did not prevent the onset of SNL-induced tactile and thermal hypersensitivity, but these signs reversed to baseline levels beginning on post-SNL day 4. Lesions of the DLF also blocked the SNL-induced increase in spinal dynorphin content, which has been suggested to promote neuropathic pain. These data distinguish mechanisms that initiate the neuropathic state as independent of descending supraspinal influences and additional mechanism(s) that require supraspinal facilitation to maintain such pain. In addition, the data indicate that these time-dependent descending influences can underlie some of the SNL-induced plasticity at the spinal level. Such time-dependent descending influences driving associated spinal changes, such as the upregulation of dynorphin, are key elements in the maintenance, but not initiation, of neuropathic states.

Fig. 1.

Lidocaine (4% w/v) or saline was microinjected bilaterally into the RVM of sham-operated male Sprague Dawley rats and of rats with L₅/L₆ SNL 3 and 6 d after nerve injury. Baseline responses to tactile and thermal stimuli were determined in sham-operated and SNL rats before injections (BL). Tactile hypersensitivity (A, C) and thermal hyperalgesia (B, D), indicated by significant decreases in the response thresholds, were measured at 10 min intervals for 60 min after each lidocaine or saline microinjection. Lidocaine did not reverse tactile hypersensitivity and thermal hyperalgesia on post-SNL day 3 (A, B) but was effective on day 6 (C, D). Behavioral responses were not altered by lidocaine in sham-operated rats or by saline in either group. *p ≤ 0.05 compared with pre-SNL values.

Fig. 2.

Lidocaine (4% w/v) or saline was microinjected bilaterally into the RVM of sham-operated male Sprague Dawley rats and of rats with L₅/L₆ SNL 3, 6, 9, and 12 d after nerve injury. Baseline responses to tactile and thermal stimuli were determined before surgery (pre-SNL) and on day 3 after surgery before injections (BL). Tactile hypersensitivity (A) and thermal hyperalgesia (B), indicated by significant decreases in the response thresholds, were measured 10 min after each lidocaine or saline microinjection. Lidocaine did not reverse tactile hypersensitivity and thermal hyperalgesia on post-SNL day 3 but was effective thereafter. Behavioral responses were not altered by lidocaine in sham-operated rats or by saline in either group. *p ≤ 0.05 compared with pre-SNL values;⁺p ≤ 0.05 compared with SNL baseline values.

Fig. 3.

Male Sprague Dawley rats received bilateral microinjections of saline or of saporin, dermorphin, or the dermorphin–saporin conjugate (Derm/Sap) (1.5 pmol on each side of the RVM). After 28 d, the rats were subjected to either L₅/L₆ SNL or sham surgery.Vertical dashed lines represent time of surgery. Paw-withdrawal thresholds to light tactile stimuli (A) and to noxious radiant heat (B) were determined before microinjections (BL), weekly after the microinjections, and daily for 14 d after SNL or sham surgery. Tactile hypersensitivity (A) and thermal hyperalgesia (B) were evident in all groups with SNL during the initial 4 d of testing, as indicated by the significant decreases in response thresholds. However, the rats pretreated with the dermorphin–saporin conjugate demonstrated clear reversal of SNL-induced threshold changes commencing at postsurgery day 5. *p ≤ 0.05 compared with premicroinjection values.

Fig. 4.

Male Sprague Dawley rats received bilateral surgical lesions of the DLF or sham DLF surgery at T₈. After 7 d, the rats were subjected to either L₅/L₆ SNL or sham surgery. Paw-withdrawal thresholds to light tactile stimuli (A) and to noxious radiant heat (B) were determined before spinal surgery before SNL (BNL) and daily for 14 d after SNL or sham surgery. Tactile hypersensitivity (A) and thermal hyperalgesia (B) were evident in all groups with SNL during the initial 4 d of testing, as indicated by the significant decreases in behavioral responses. However, the rats that received both L₅/L₆ SNL and lesions of the DLF demonstrated a clear reversal of SNL-induced threshold changes commencing at postsurgery days 4–5. *p ≤ 0.05 compared with premicroinjection values. N, Naive.

Fig. 5.

The spinal cords of sham-operated rats (sham SNL) and rats with L₅/L₆ SNL that had received either lesions of the DLF or sham spinal surgery (sham DLF) were removed on day 10 after surgery. The dorsal half of the lumbar cord was isolated and assayed for dynorphin content with enzyme immunoassay. The rats with SNL that had also received sham DLF surgery showed a significant (p ≤ 0.05; Student'st test) increase in spinal dynorphin content when compared with the sham SNL/sham DLF group. In contrast, the spinal dynorphin content of the rats with SNL or sham SNL that also received lesions of the DLF was not significantly different (p > 0.05; Student's ttest) than that of the SNL/sham DLF group.