Enhanced descending modulation of nociception in rats with persistent hindpaw inflammation

1. The role of descending brain stem modulatory systems in the development of persistent behavioral hyperalgesia and dorsal horn hyperexcitability was studied in rats with unilateral hindpaw inflammation. Inflammation was induced by intraplantar injection of complete Freund's adjuvant (CFA, 0.05 ml of an 1:1 oil/saline emulsion, 25 mu g Mycobacterium), or lambda carrageenan (1 mg/0.1 ml saline). Thermal hyperalgesia was assessed by testing paw withdrawal latency (PWL) to a noxious heat stimulus. Superficial dorsal horn nociceptive (nociceptive specific, NS, and wide dynamic range, WDR) neuronal activity in the lumbar spinal cord was recorded extracellularly in chloralose-anesthetized rats. 2. Bilateral lesions of the dorsolateral funiculus (DLFX) at the T10 level were made in 13 rats, and the development of thermal hyperalgesia in these rats was compared with sham-operated or nonoperated control rats. Ln rats receiving a 0.05-ml CFA injection, a similar magnitude of hyperalgesia developed in the inflamed paw in DLFX (n = 7) and control (n = 8) rats. In addition, there appeared to be a contralateral hyperalgesia that was most apparent between 2 and 24 h after injection of CFA in DLFX rats. The CFA-induced contralateral effects were significantly different (P < 0.05) from the control rats at 2 and 6 h. 3. The intensity of the thermal stimulus was reduced and a low dose of carrageenan (1 mg) was injected into one hindpaw to further reveal the potentiation of hyperalgesia in DLFX rats. Throughout the 0.5- to 4-h time period after the injection of carrageenan, the PWL of the inflamed paws in DLFX rats (n = 6) was significantly shorter than that of control rats (n = 10; 2-way analysis of variance, F-1.14, = 14.04, P < 0.01), suggesting the enhancement of hyperalgesia in DLFX rats. A hyperalgesia on the noninflamed paws was also more apparent in this experiment in DLFX rats, when compared with control rats. DLFX did not affect the baseline PWL of the rats. 4. A reversible spinalization was produced by application of a local anesthetic, lidocaine (2%, 0.1 ml), onto the dorsal surface of the thoracic cord (T10-12). This procedure produced thoracic spinal block that lasted for 90 min. The effects of thoracic lidocaine block on nociceptive neuronal activity were studied in 11 neurons (NS = 7, WDR = 4) in CFA-inflamed rats and 10 neurons (NS = 6, WDR = 4) in noninflamed naive rats. After the thoracic lidocaine block, rats showed increases in background activity, expansion of the receptive fields, and increased responses to noxious thermal, mechanical, and electrical stimuli. 5. Quantitative comparison revealed that the mean change in background firing rate of dorsal horn neurons was greater in inflamed [NS: 18.3 +/- 0.4 Hz, (mean +/- SE) n = 7; WDR: 10.9 +/- 0.7 Hz, n = 4] than that in noninflamed (NS: 2.3 +/- 0.3 Hz, n = 6; WDR: 3.3 +/- 0.4 Hz, n = 4) rats (P < 0.01, t-test) after thoracic lidocaine block. Thoracic saline application produced a 2.8 +/- 0.4 Hz decrease in background activity (2 NS and 2 WDR units). The expansion of the receptive fields after thoracic lidocaine block was also greater in inflamed (NS: 141 +/- 9% control, n = 6; WDR: 240 +/- 36% control, n = 4) than in noninflamed (NS: 114 +/- 9% control, n = 6; WDR: 167 +/- 21% control, n = 4) rats (P < 0.05, t-test). Thoracic saline did not produce a significant change in the receptive field size (105 +/- 9%, n = 4). The increases in responses to noxious thermal and mechanical stimuli after thoracic lidocaine block were also significantly greater in inflamed than in noninflamed rats (P < 0.01). There was no significant difference in the increase in responses to electrical stimulation of the sciatic nerve after Lidocaine between inflamed and noninflamed rats. 6. A local anesthetic block was produced by microinjection of lidocaine (2%, 0.5 mu l) into the medial rostroventral medulla, primarily the nucleus raphe magnus (NRM), and the changes in nociceptive neuronal activity (NS = 8, WDR = 5) were studied in CFA-inflamed rats. After the NRM lidocaine block, increased neuronal activity was observed in the majority of neurons, although reduced responsiveness also was seen. The effects of NRM lidocaine appeared 10 min after the injection and lasted for greater than or equal to 90 min. There were increases in background activity from 4.3 +/- 0.9 to 6.9 +/- 1.3 Hz (n = 13, P < 0.05), receptive field size from 248 +/- 50 to 308 +/- 52 mm(2) (n = 13, P < 0.05), noxious thermal responses from 279 +/- 46 to 721 +/- 153 impulses (n = 12, P < 0.01), and noxious pinch-evoked responses from 311 +/- 73 to 494 +/- 88 impulses (n = 13, P < 0.05). The increase in electrical stimulus-evoked responses after lidocaine did not reach statistical significance. The injection of saline (0.5 ml) into the NRM (n = 3) or lidocaine into the areas of the predorsal bundle (n = 1) or perifacial zone (n = 2) did not produce significant changes in neuronal activity. 7. The present study provides convergent behavioral and electrophysiological evidence that the blockade of the brain stem spinal descending pathways results in potentiation of behavioral hyperalgesia and dorsal horn hyperexcitability in rats with hindpaw inflammation. Quantitative comparison between inflamed and noninflamed rats revealed an enhanced net descending inhibition as a result of inflammation. The results of local anesthesia of the NRM suggest that this site of descending modulation is a source of enhanced net tonic inhibitory modulation in inflamed animals. The brain stem descending input to the spinal cord will dampen or counteract the cascade of events that ultimately lead to the development of inflammatory hyperalgesia.