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ANALGESIA

The Antiallodynic Effect of Neurotropin® Is Mediated via Activation of Descending Pain Inhibitory Systems in Rats with Spinal Nerve Ligation

From the Department of Development Research, Institute of Bio-active Science, Nippon Zoki Pharmaceutical Co., Ltd., 442-1, Kinashi, Kato, Hyogo, 673-1461, Japan.

Abstract

BACKGROUND: Neurotropin®, a nonprotein extract isolated from inflamed skin of rabbits inoculated with vaccinia virus, is widely used in Japan to treat chronic pain such as neuropathic pain. Although some studies have been conducted on the mechanism of the antiallodynic action of Neurotropin, this mechanism has yet to be adequately clarified.

METHODS: The left fifth lumbar nerve of rats was tightly ligated with silk sutures under pentobarbital anesthesia. Mechanical allodynia was confirmed by measuring the hindpaw withdrawal threshold in response to application of von Frey filaments. Behavioral tests were performed at 28 days after nerve ligation. Neurotropin was administered IV, intrathecally or intracerebroventricularly in L5 spinal nerve ligation (L5-SNL) rats. We examined the effects of noradrenergic, serotonergic and -aminobutyric acid (GABA)ergic antagonists on the antiallodynic action of Neurotropin in L5-SNL rats. Yohimbine hydrochloride (yohimbine) was used as an ₂ adrenoceptor antagonist, ketanserin tartrate (ketanserin) as a 5-HT_2A receptor antagonist, MDL72,222 as a 5-HT₃ receptor antagonist, (-)-bicuculline methobromide (bicuculline) as a GABA_A receptor antagonist, and CGP35,348 as a GABA_B receptor antagonist, and intrathecally injected.

RESULTS: IV (50–100 NU/kg) doses of Neurotropin elicited an antiallodynic action in L5-SNL rats. Moreover, intracerebroventricular (400 mNU/rat), but not intrathecal, injection of Neurotropin inhibited allodynia. The antiallodynic action of Neurotropin (100 NU/kg, IV) was antagonized by intrathecal injections of yohimbine (10 nmol/rat), ketanserin (30 nmol/rat), MDL72,222(30 nmol/rat), bicuculline (0.6 nmol/rat) and CGP35348 (30 nmol/rat). On the other hand, the antiallodynic action of intrathecally injected m-CPBG (5-HT₃ receptor agonist) was reversed by intrathecal injection of bicuculline and CGP35348, suggesting interaction of 5-HT₃ receptors and spinal inhibitory (GABAergic) interneurons.

CONCLUSIONS: These results suggest that the antiallodynic effect of Neurotropin is mediated via activation of descending pain inhibitory systems, such as the noradrenergic and serotonergic systems, which project from supraspinal sites to the spinal dorsal horn. In addition, activation of inhibitory GABAergic interneurons via 5-HT₃ receptors by serotonin released in the spinal dorsal horn may also be involved in the antiallodynic action of Neurotropin.