It is documented that spinal nociceptive transmission receives descending facilitatory and inhibitory modulation from supraspinal structures. The rostral ventral medulla (RVM), including the nucleus raphe magnus (NRM), nuclei reticularis gigantocellularis (NGC) and gigantocellularis pars alpha (NGCalpha), is the major bulbar relay of descending modulatory influences. Pharmacological studies show that facilitation of a spinal nociceptive tail-flick (TF) reflex induced by stimulation in the NGC and NGCalpha is mediated by spinal serotonergic receptors. The present series of experiments provide evidence that activation of spinal serotonergic systems are critical for both induction and maintenance of secondary hyperalgesia induced by subcutaneous injection of formalin into one hindpaw. Subcutaneous injection of formalin produced facilitation of tail withdrawal (mechanical) and the TF reflex (thermal). Facilitatory effects persisted for at least 30 min. Peripheral blockade of the activity by local injection of a hydrophilic lidocaine derivative (QX-314, 5%) into the injected hindpaw abolished both mechanical and thermal facilitation, indicating that peripheral input is important to maintain long-lasting facilitation. Intrathecal application of a serotonergic receptor antagonist methysergide at a dose (64 nmol) which completely blocked descending facilitation produced by electrical- or chemical-stimulation in the NGC and NGCalpha also significantly attenuated or completely abolished facilitation of tail withdrawal and the TF reflex induced by formalin. Methysergide was effective whether the injection was performed before or after the formalin injection. These results suggest that activation of descending facilitatory serotonergic influences by a prolonged noxious stimulation could contribute to secondary hyperalgesia observed at the tail.
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