strychnine and Hyperesthesia

Intrathecal strychnine (glycine antagonist) or bicuculline (GABA(A) antagonist) yields a touch-evoked agitation that is blocked by N-methyl-D-aspartate receptor antagonism. We examined the effects of intrathecal strychnine and bicuculline on touch-evoked agitation and the spinal release of amino acids. Fifty-two Sprague-Dawley rats were prepared under halothane anesthesia with a lumbar intrathecal catheter and a loop dialysis catheter. Four days after implantation, rats were randomized to receive an intrathecal injection of N-methyl-D-aspartate (3 microg), strychnine (3 microg) or bicuculline (10 microg), or a combination of N-methyl-D-aspartate with bicuculline or strychnine. The agitation produced by brief light tactile stroking of the flank (tactile allodynia), and the spontaneous spinal release of glutamate, taurine and serine was measured. Intrathecal N-methyl-D-aspartate, strychnine and bicuculline produced similar touch-evoked allodynia. Intrathecal bicuculline and N-methyl-D-aspartate alone evoked a transient spinal release of glutamate and taurine, but not serine, in the 0- 10 min sample, while strychnine did not affect spinal transmitter release at any time. As GABA(A) but not glycine receptor inhibition at equi-allodynic doses increases glutamate release, while the allodynia of both is blocked by N-methyl-D-aspartate receptor antagonism, we hypothesize that GABA(A) sites regulate presynaptic glutamate release, while glycine regulates the excitability of neurons postsynaptic to glutamatergic terminals.

Topics: Amino Acids; Animals; Behavior, Animal; Bicuculline; Excitatory Amino Acid Agonists; GABA Antagonists; GABA-A Receptor Antagonists; Glycine Agents; Hyperesthesia; Male; N-Methylaspartate; Rats; Rats, Sprague-Dawley; Receptors, Glycine; Spinal Cord; Strychnine; Touch

The blockade of spinal glycine receptors with intrathecal (i.t.) strychnine produces segmentally-localized allodynia in the rat; a reversible and highly reproducible effect that is attained without peripheral or central nerve injury. We investigated the effect of i.v. mexiletine, an orally active congener of lidocaine, on strychnine allodynia and compared the dose-response relationship of mexiletine in normal (noxious paw pinch) versus abnormal (i.t. strychnine) nociceptive conditions. In addition, we determined the dose-response effect of i.t. AP-7 (an NMDA antagonist) on strychnine allodynia. Male, Sprague-Dawley rats, fitted with chronic i.t. catheters, were lightly anesthetized with urethane. Stimulus evoked changes in blood pressure and heart rate were recorded from the left carotid artery and cortical electroence-phalographic (EEG) activity was continuously monitored using subdermal needle electrodes. After i.t. strychnine (40 micrograms), repetitive brushing of the hair (hair deflection) evoked a progressive increase in mean arterial pressure and heart rate, an abrupt motor withdrawal response, and desynchronization of the EEG, equivalent to those elicited by the chemical nociceptive agent, mustard oil (without strychnine). Pretreatment with mexiletine (5-30 mg/kg i.v. 5 min before i.t. strychnine) dose-dependently inhibited the responses evoked by noxious hind paw pinch (no strychnine) and hair deflection (after i.t. strychnine) with equal potency (ED50's = 9.1-17 mg/kg). Below 30 mg/kg, this effect was achieved without a change in EEG synchrony (cortical activity reflecting the level of anesthesia) and without affecting motor efferent pathways. Strychnine allodynia was also significantly blocked by i.t. AP-7. The ED50's and 95% confidence intervals were 1.1 micrograms (0.7-1.8) for mean arterial pressure, 1.7 micrograms (0.5-6.0) for heart rate, and 0.4 microgram (0.07-2.0) for withdrawal duration. Cortical EEG synchrony was unchanged after i.t. AP-7 consistent with a spinal site of action. The data indicate that: (i) robust allodynia can be selectively induced with i.t. strychnine in animals whose somatosensory systems are otherwise normal; (ii) sub-anesthetic doses of i.v. mexiletine inhibit the abnormal responses to low-threshold (A-fiber) afferent input in the strychnine model of allodynia (i.e., in the absence of peripheral or central nerve injury) at doses which affect normal nociception; and (iii) in the presence of i.t. strychnine, low-th

Topics: 2-Amino-5-phosphonovalerate; Animals; Dose-Response Relationship, Drug; Foot; Hyperesthesia; Male; Mexiletine; Nociceptors; Pain; Physical Stimulation; Rats; Rats, Sprague-Dawley; Strychnine

A rare case of suicidal strychnine poisoning that resolved naturally without treatment is presented. The patient first complained of chest pain, which was originally thought to be caused by a dissecting aneurysm; however, nystagmus, dysesthesia, spastic paraplesia, and hyperreactivity to stimuli shortly developed. Diagnosis was difficult because the patient did not disclose the drinking of strychnine or the suicidal intent, and no abnormal signs were seen in the various central nervous system examinations. The natural course was observed without treatment because the patient's circulatory and respiratory condition was good. Movement disturbances in the upper extremities disappeared after 2 days, nystagmus in 3 days, and dysesthesia and spastic paraplesia in 4 days. The patient was able to stand on the fourth day and walk on the seventh. He was discharged on day 10 without any detectable ill effects.

Topics: Central Nervous System Diseases; Diagnosis, Differential; Humans; Hyperesthesia; Male; Middle Aged; Muscle Spasticity; Paraplegia; Poisoning; Strychnine; Suicide, Attempted

The intrathecal administration of strychnine in rats yields a prominent touch-evoked allodynia. The effects of an intrathecally administered A1 adenosine agonist: N6-(L-2-phenylisopropyl)-adenosine (LPIA) or an A2 adenosine agonist: 5'-(N-ethyl carboxamido)-adenosine (NECA), on this touch-evoked hyperesthesia were examined. Over the range of 0.3-1.0 nmol these agents produced a dose-dependent inhibition of the strychnine-evoked hyperesthesia. This inhibition was reversed following intraperitoneal injection of caffeine, an adenosine receptor antagonist. No statistical differences between LPIA and NECA were recorded. The powerful effect of adenosine analogues on strychnine hyperesthesia occur at doses that have only a mild analgesic effect on the thermally evoked hot-plate response. This effect is in contrast to opioids, which have been reported to be only minimally effective against strychnine-evoked hyperesthesia. The characteristics of the strychnine hyperesthesia appear to mimic the clinical phenomenon observed in patients suffering from sensory dysesthesia following nerve injury and suggest a possible role for the adenosine receptor in certain pain states.

Topics: Animals; Hyperesthesia; Injections, Spinal; Male; Rats; Rats, Inbred Strains; Receptors, Glycine; Receptors, Neurotransmitter; Receptors, Purinergic; Spinal Cord; Strychnine

In rats with chronically implanted intrathecal catheters, high concentrations of morphine (3 microliters of 50 mg/ml: 150 micrograms) yielded a reliable and striking syndrome of pain behavior that involved intermittent bouts of biting and scratching at the dermatomes innervated by levels of the spinal cord proximal to the catheter tip. In addition, during intervals between bouts of agitation, the animals displayed a clear, marked hyperesthesia where an otherwise innocuous stimuli (brush stroke) evoked significant signs of discomfort and consequent aggressive behavior. These effects were exaggerated rather than reversed by high doses of naltrexone. The effect, perfectly mimicked by a considerably lower dose of morphine-3-glucuronide (15 micrograms) or the glycine antagonist strychnine (30 micrograms), was not produced by equimolar concentrations of sodium sulfate, glucuronide, methadone, or sufentanil. In halothane-anesthetized cats, light brushing of the hindpaw and tail or low-intensity stimulation of the sciatic nerves resulted in prominent elevations in blood pressure and pupil diameter following the intrathecal administration of high concentrations (50 mg/ml; 0.1 ml) of morphine sulfate. This effect, exaggerated by naloxone, was produced by a lower concentration of intrathecal morphine-3-glucuronide (5 mg/ml; 0.1 ml) but not by intrathecal saline. These results suggest the possibility that the effects of high doses of morphine may be characterized by a nonopiate receptor-mediated effect that alters the coding of sensory information in the spinal cord. The authors speculate that high concentrations of spinal opiates, as may be employed in tolerant terminal-cancer patients, could exert an action that physiologically antagonizes the analgesic effects otherwise mediated by the action of morphine on the spinal opiate receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anesthesia, Spinal; Animals; Blood Pressure; Cats; Drug Tolerance; Fentanyl; Hyperesthesia; Methadone; Morphine; Morphine Derivatives; Naltrexone; Rats; Receptors, Drug; Stimulation, Chemical; Strychnine; Sufentanil; Sulfates; Touch

Glycine or its receptor antagonist, strychnine, were administered perispinally to investigate their effect on nociceptive responses elicited by activation of various cutaneous receptors. Strychnine produced dose-dependent sensory and motor disturbances; 1 and 5 micrograms doses were sub-convulsive, eliciting recurrent episodes of coordinated grooming, scratching and biting at the skin, which persisted for approximately 10 minutes post-injection; higher doses (25 and 100 micrograms) increased the intensity and duration of these effects, and produced convulsive motor seizures. Motor disturbances were not elicited by glycine (5, 25, 100 and 400 micrograms). Strychnine treated rats, at all doses, vocalized consistently in response to light cutaneous stimulation; a significant proportion of glycine treated rats also vocalized, but were not as sensitive to mild stimulation. Skin hyperalgesia persisted for at least 30 minutes in both strychnine and glycine treated rats. Both strychnine and glycine significantly reduced vocalization thresholds to tail shock. However, no clear effect on tail flick latency was observed following either strychnine or glycine. These results indicate that glycinergic neurons contribute to the tonic regulation of nociceptive input at the spinal cord.

Topics: Animals; Behavior, Animal; Castration; Female; Glycine; Hyperalgesia; Hyperesthesia; Injections, Spinal; Pain; Physical Stimulation; Rats; Rats, Inbred Strains; Seizures; Sensory Thresholds; Spinal Cord; Strychnine; Vocalization, Animal

Topics: Animals; Cerebral Decortication; Cordotomy; Ganglia, Spinal; Haplorhini; Hyperesthesia; Macaca; Motor Cortex; Neural Inhibition; Skin; Spinal Cord; Spinal Nerve Roots; Strychnine; Synaptic Transmission