ABSTRACT-The pain response of mice to an injection of 0.5% formalin into the dorsal surface of a hindpaw is biphasic, with a first phase lasting for 5 min and a second phase lasting from 10 to 30 min post-injection. Intrathecal (i.t.) injection of [D-Pro2, D-Trp7'9]-substance P inhibited the first phase, and i.t. cysteamine inhibited the second phase. Lappaconitine (LA) and morphine (MOR) inhibited both phases equally in a dose-dependent manner. Diclofenac inhibited both phases, but the second phase was inhibited by lower doses. An Lt. injection of substance P (SP) or somato statin (SOM) produced a characteristic behavioral response (scratching, biting, and licking). This behavioral response to SP and SOM was inhibited by s.c., intracerebro ventricular (i.c.v.), or Lt. injection of MOR. In contrast, LA inhibited the SP and SOM-induced response when injected s.c. or i.c.v., but had no effect when injected intrathecally. These results indicate that LA may act supraspinally to inhibit the trans mission of nociceptive information by SP and/or SOM.Substance P (SP) and somatostatin (SOM) have been shown to be localized in the dorsal horn of the spinal cord (1, 2) and much evi dence suggests a role for SP and SOM as possible mediators for pain transmission, as reviewed by Sweet (3) and Luttinger et al. (4).The formalin test was originally described in rats and cats by Dubuisson and Dennis (5); the injection of formalin produced a biphasic pain response in rats. Takahashi et al. (6) and Hunskaar et al. (7) reported a slightly modi fied formalin test in mice and examined the effects of many narcotic analgesics, centrally acting non-narcotic analgesics, steroidal antiin flammatory drugs, and non-steroidal antiin flammatory drugs (NSAIDs) (8, 9). Based on these reports, it has been concluded that the biphasic response induced by the injection of formalin reflects the operation of different nociceptive mechanisms. The first phase is due to a direct effect on nociceptors, and the second phase may be due mainly to subse quent inflammation. Takagi and Kuraishi (10), and Kantner et al. (11) showed that SP and SOM were released from the dorsal horn in response to formalin injection, and Ohkubo et al. (12) showed that intrathecal (i.t.) injection of SP antagonist and SP antiserum inhibited only the first phase, while i.t. injection of SOM antagonist and SOM antiserum inhibited only the second phase. These facts indicate that SP is involved in the transmission of the first phase and that SOM is involved in the transmission of the second phase of formalin

Systemic and intracerebroventricular (i.c.v.) injections of lappaconitine (LA) produced a dose-dependent inhibition of the response to thermal stimulation in sham-operated mice as assayed by the tail-immersion test. After spinal transection, the antinociceptive potencies of s.c. or i.c.v.-administered LA were markedly re duced. Antinociception induced by systemically administered LA was clearly reduced by pretreatment with 6-hydroxydopamine or 5,7-dihydroxytryptamine through the i.c.v. and intrathecal (i.t.) routes. When LA was administered by 1. c.v. -injection, the LA-induced antinociception was reduced by pretreatment with timolol, a Q-adrenergic antagonist, and ketanserin, a 5-HT2 antagonist. Administration of LA by the i.t. route resulted in a significant antinociceptive activity, which was also reduced by pretreat ment with phenoxybenzamine, an a-adrenergic antagonist, and mianserin, a 5-HT1 antagonist. The results of these studies suggest that the central noradrenergic and serotonergic systems may be involved in the antinociception of systemically adminis tered LA, and these pathways are mediated by /9-adrenoceptors and 5-HT2 receptors in the brain and a-adrenoceptors and 5-HT, receptors in the spinal cord.In a previous paper, we demonstrated that lappaconitine (LA) had naloxone-resistant analgesic effects (1). Furthermore, we re ported that a supraspinal-spinal interaction was important for the production of the anti nociceptive action of systemically administered LA (2) and that LA acted at the supraspinal level to inhibit nociceptive transmission or to block the spinal action of nociceptive neuro transmitters via the descending pathways (3).It is well-known that the descending inhibi tory systems play an important role in pain modulation and analgesia, and central norad renergic and serotonergic pathways, particular ly bulbospinal pathways, may modulate the transmission in these systems (4, 5).The purpose of the present study was to ex amine the role of central noradrenergic and serotonergic systems in the antinociceptive ac tion of LA. MATERIALS AND METHODS AnimalsMale mice of the Std:ddY strain, weighing 20 to 30 g, were used. Mice were maintained in a temperature and humidity-controlled room (22-23T, 50-60%) and allowed free access to food and water.

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