Brainstem injection of lidocaine releases the descending pain-inhibitory mechanisms in a rat model of mononeuropathy.

Lidocaine injections in the rostral ventromedial medulla (RVM) have been shown to produce significant reduction of neuropathic manifestations in rats. This effect has been attributed to selective block of a pain descending facilitatory system, responsible for chronic pain. However, recent observations from our laboratory did not provide confirmation to this hypothesis. We aimed, therefore, to investigate the spinal synaptic mechanisms activated by lidocaine injections in the RVM. Rats were subjected, under deep anesthesia, to the induction of mononeuropathy on one hindpaw, and to the stereotaxic implantation of chronic cannulae in the RVM for the injection of lidocaine or GABA antagonists. Implanted intrathecal catheter in the lumbosacral space was used for the injection of specific antagonists to GABA, 5HT, glycine, noreadrenaline and dopamine, prior to lidocaine. Tactile and cold hyperreactivity and heat hyperalgesia were assessed using von Frey hair filaments, acetone drop test and heat-induced paw withdrawal, respectively. Lidocaine injections produced significant inhibition of all neuropathic manifestations. Intrathecal injection of antagonists to GABA (bicucullin, picrotoxin and saclofen), serotonin 5HT(1-2) (ketanserin and methysergide) and α- (phentoalmine, yohimbine) and ß- (propranolol) adrenergic receptors, suppressed the lidocaine inhibitory effects; while partial or no attenuation were observed following pretreatment with glycine and dopamine D(2/3) antagonists. Comparable effects were observed with RVM injection of GABA antagonists. Lidocaine injection in the RVM results in a release of the descending pain-inhibitory systems from a tonic gabaergic inhibition. This descending system involves the activation of gabaergic, serotonergic and adrenergic mechanisms at the level of the spinal dorsal horn.

Alteration of GABAergic and glycinergic mechanisms by lidocaine injection in the rostral ventromedial medulla of neuropathic rats.

Attenuation of neuropathic manifestations in experimental animals, by lidocaine injection in the rostral ventro-medial medulla (RVM), has been traditionally attributed to selective block of a descending pain facilitatory system. However, the presence of descending fibers carrying this effect and the selective action of lidocaine on the facilitatory neurons, have not been supported by convincing experimental evidence. The present study aimed to investigate the mechanisms underlying the hypoalgesic action of lidocaine injection in the brainstem. Several groups of rats were subjected to mononeuropathy on their left hind paws, according to the model of spared nerve injury, and were subsequently implanted with guide cannulae in the RVM. After recovery, rats received injections of lidocaine, GABA and glycine agonists or antagonists and their effects were assessed on behavioral tests of allodynia and hyperalgesia. Injections of lidocaine at doses ranging between 0.05% and 2% produced attenuation at high doses and no effects or increasing hyperalgesia at low doses. GABA and glycine agonists increased neuropathic manifestations while their antagonists elicited the opposite effects. A combined injection of GABA agonist or glycine with lidocaine (0.5%) prevented the inhibitory effects of lidocaine injection alone. Our results are in line with the abundant documentation on the alteration of the function of inhibitory neurons by lidocaine and reveal a possible action of the injected high doses on the GABAergic and glycinergic neurons in the RVM. The resulting block of the inhibitory tone exerted by these neurons can lead to a release of the descending pain inhibitory systems.