ENHANCED DESCENDING MODULATION OF NOCICEPTION IN RATS WITH PERSISTENTHINDPAW INFLAMMATION

1. The role of descending brain stem modulatory systems in the develop ment of persistent behavioral hyperalgesia and dorsal horn hyperexcita bility was studied in rats with unilateral hindpaw inflammation. Infla mmation was induced by intraplantar injection of complete Freund's adj uvant (CFA, 0.05 ml of an 1:1 oil/saline emulsion, 25 mu g Mycobacteri um), 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 spina l cord was recorded extracellularly in chloralose-anesthetized rats. 2 . Bilateral lesions of the dorsolateral funiculus (DLFX) at the T10 le vel were made in 13 rats, and the development of thermal hyperalgesia in these rats was compared with sham-operated or nonoperated control r ats. Ln rats receiving a 0.05-ml CFA injection, a similar magnitude of hyperalgesia developed in the inflamed paw in DLFX (n = 7) and contro l (n = 8) rats. In addition, there appeared to be a contralateral hype ralgesia that was most apparent between 2 and 24 h after injection of CFA in DLFX rats. The CFA-induced contralateral effects were significa ntly different (P < 0.05) from the control rats at 2 and 6 h. 3. The i ntensity of the thermal stimulus was reduced and a low dose of carrage enan (1 mg) was injected into one hindpaw to further reveal the potent iation of hyperalgesia in DLFX rats. Throughout the 0.5- to 4-h time p eriod after the injection of carrageenan, the PWL of the inflamed paws in DLFX rats (n = 6) was significantly shorter than that of control r ats (n = 10; 2-way analysis of variance, F-1.14, = 14.04, P < 0.01), s uggesting 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 ba seline PWL of the rats. 4. A reversible spinalization was produced by application of a local anesthetic, lidocaine (2%, 0.1 ml), onto the do rsal surface of the thoracic cord (T10-12). This procedure produced th oracic spinal block that lasted for 90 min. The effects of thoracic li docaine block on nociceptive neuronal activity were studied in 11 neur ons (NS = 7, WDR = 4) in CFA-inflamed rats and 10 neurons (NS = 6, WDR = 4) in noninflamed naive rats. After the thoracic lidocaine block, r ats showed increases in background activity, expansion of the receptiv e 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 lidocain e block. Thoracic saline application produced a 2.8 +/- 0.4 Hz decreas e in background activity (2 NS and 2 WDR units). The expansion of the receptive fields after thoracic lidocaine block was also greater in in flamed (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 prod uce a significant change in the receptive field size (105 +/- 9%, n = 4). The increases in responses to noxious thermal and mechanical stimu li after thoracic lidocaine block were also significantly greater in i nflamed than in noninflamed rats (P < 0.01). There was no significant difference in the increase in responses to electrical stimulation of t he sciatic nerve after Lidocaine between inflamed and noninflamed rats . 6. A local anesthetic block was produced by microinjection of lidoca ine (2%, 0.5 mu l) into the medial rostroventral medulla, primarily th e nucleus raphe magnus (NRM), and the changes in nociceptive neuronal activity (NS = 8, WDR = 5) were studied in CFA-inflamed rats. After th e NRM lidocaine block, increased neuronal activity was observed in the majority of neurons, although reduced responsiveness also was seen. T he effects of NRM lidocaine appeared 10 min after the injection and la sted for greater than or equal to 90 min. There were increases in back ground 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 impul ses (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 electr ical stimulus-evoked responses after lidocaine did not reach statistic al 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 perifa cial zone (n = 2) did not produce significant changes in neuronal acti vity. 7. The present study provides convergent behavioral and electrop hysiological evidence that the blockade of the brain stem spinal desce nding pathways results in potentiation of behavioral hyperalgesia and dorsal horn hyperexcitability in rats with hindpaw inflammation. Quant itative comparison between inflamed and noninflamed rats revealed an e nhanced net descending inhibition as a result of inflammation. The res ults of local anesthesia of the NRM suggest that this site of descendi ng modulation is a source of enhanced net tonic inhibitory modulation in inflamed animals. The brain stem descending input to the spinal cor d will dampen or counteract the cascade of events that ultimately lead to the development of inflammatory hyperalgesia.