The Anti-Allodynic Effects of Amitriptyline, Gabapentin, and Lidocaine in a Rat Model of Neuropathic Pain

The management of patients with neuropathic pain is challenging.There are only a few reports regarding the acute effects of the commonly used adjuvant drugs amitriptyline (AMI), gabapentin (GBP), and lidocaine (LDC) on neuropathic pain behaviors in animal models. Thus, the purpose of this study was to investigate the acute effects of AMI, GBP, and LDC on behavioral signs of mechanical allodynia and the site of action of these drugs using a rat model of neuropathic pain. Under general anesthesia with halothane, neuropathic injury was produced in rats by tightly ligating the left L5 and L6 spinal nerves. In Experiment 1, baseline mechanical allodynia data were recorded, and the animals were randomly divided into five groups: Group 1 received saline intraperitoneally (IP), Group 2 received AMI (1.5 mg/kg IP); Group 3 received GBP (50 mg/kg IP), Group 4 received an IV saline infusion for 10 min, and Group 5 received LDC (10-mg/kg IV infusion) for 10 min. Measurements of mechanical allodynia were repeated 0.5, 1, 2, and 4 h and 1, 3, and 7 days after treatment. In Experiment 2, rats were prepared similarly to the first experiment, and a single unit activity of continuous discharges of injured afferent fibers was recorded from the left L5 fascicles before and until 1 h after treatment. All animals developed neuropathic pain behavior within 7 days after surgery. All three tested drugs were effective in increasing the threshold for mechanical allodynia as early as 30 min after treatment, and the effect lasted for at least 1 h. Furthermore, AMI and LDC reduced the rate of continuing discharges of injured afferent fibers, whereas GBP did not influence these discharges. Our findings clearly demonstrate an attenuation of neuropathic pain behavior in rats treated with AMI, GBP, or LDC. Finally, the site of action of LDC seems to be primarily in the periphery, and that of GBP is exclusively central, whereas that of AMI seems to have both peripheral and central components. Implications: In the present study, we examined the effectiveness of three drugs commonly used for the treatment of neuropathic pain. Systemic injections of amitriptyline, gabapentin, or lidocaine produced pain-relieving effects in this established model for neuropathic pain in rats, which supports their clinical use in managing patients with neuropathic pain syndromes. (Anesth Analg 1998;87:1360-6)

[1]  A. Dickenson,et al.  Effects of systemic carbamazepine and gabapentin on spinal neuronal responses in spinal nerve ligated rats , 1998, Pain.

[2]  D. Ardid,et al.  Antinociceptive effects of acute and ‘chronic’ injections of tricyclic antidepressant drugs in a new model of mononeuropathy in rats , 1992, Pain.

[3]  H. Na,et al.  Contributions of injured and intact afferents to neuropathic pain in an experimental rat model , 1996, Pain.

[4]  M. McLean.  Clinical pharmacokinetics of gabapentin , 1994, Neurology.

[5]  L. Gugino,et al.  Central Effects of Local Anesthetic Agents , 1987 .

[6]  J. Eisenach,et al.  Intrathecal Amitriptyline Acts as an N‐Methyl‐D‐Aspartate Receptor Antagonist in the Presence of Inflammatory Hyperalgesia in Rats , 1995, Anesthesiology.

[7]  B. Oberg,et al.  Studies on the endoanesthetic effects of lidocaine and benzonatate on non-medullated nerve endings in the left ventricle. , 1981, Acta physiologica Scandinavica.

[8]  Jin Mo Chung,et al.  An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat , 1992, PAIN.

[9]  P. Keck,et al.  Comorbidity of migraine and panic disorder , 1994, Neurology.

[10]  T. Yaksh,et al.  Effect of Subarachnoid Gabapentin on Tactile‐Evoked Allodynia in a Surgically Induced Neuropathic Pain Model in the Rat , 1997, Regional anesthesia.

[11]  D. Bowsher.  Neurogenic pain syndromes and their management. , 1991, British medical bulletin.

[12]  H. Rosner,et al.  Gabapentin adjunctive therapy in neuropathic pain states. , 1996, The Clinical journal of pain.

[13]  R. Ramsay.  Clinical efficacy and safety of gabapentin , 1994, Neurology.

[14]  Y. Sharav,et al.  Autotomy behavior in rats following peripheral deafferentation is suppressed by daily injections of amitriptyline, diazepam and saline , 1989, Pain.

[15]  D. Oxender,et al.  Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA , 1995, Epilepsy Research.

[16]  M. Nakata,et al.  Differential action of amitriptyline on neurons in the trigeminal nucleus , 1991, Neurology.

[17]  C. Carter,et al.  Inhibition of synaptosomal veratridine-induced sodium influx by antidepressants and neuroleptics used in chronic pain , 1996, Neuroscience Letters.

[18]  G. Pasternak,et al.  Analgesic activity of tricyclic antidepressants , 1983, Annals of neurology.

[19]  E. U. Kölle,et al.  Pharmacokinetics and metabolism of gabapentin in rat, dog and man. , 1986, Arzneimittel-Forschung.

[20]  J. Kocsis,et al.  A summary of mechanistic hypotheses of gabapentin pharmacology , 1998, Epilepsy Research.

[21]  T. Yaksh,et al.  Quantitative assessment of tactile allodynia in the rat paw , 1994, Journal of Neuroscience Methods.

[22]  M. Rowbotham.  Chronic pain , 1995, Neurology.

[23]  M. Devor,et al.  Modulation of activity in dorsal root ganglion neurons by sympathetic activation in nerve-injured rats. , 1994, Journal of neurophysiology.

[24]  S L Shafer,et al.  Prolonged Alleviation of Tactile Allodynia by Intravenous Lidocaine in Neuropathic Rats , 1995, Anesthesiology.

[25]  R. Burney,et al.  Intravenous Lidocaine in the Management of Various Chronic Pain States: A Review of 211 Cases , 1985, Regional Anesthesia & Pain Medicine.

[26]  Gary J. Bennett,et al.  Painful neuropathy: altered central processing maintained dynamically by peripheral input , 1992, Pain.

[27]  Amitriptyline, but not lorazepam, relieves postherpetic neuralgia , 1988, Neurology.

[28]  P. Wall,et al.  Relative effectiveness of C primary afferent fibers of different origins in evoking a prolonged facilitation of the flexor reflex in the rat , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[29]  W D Willis,et al.  Cutaneous sensory receptors in the rat foot. , 1993, Journal of neurophysiology.

[30]  C. Woolf,et al.  The systemic administration of local anaesthetics produces a selective depression of C-afferent fibre evoked activity in the spinal cord , 1985, Pain.

[31]  T. Yaksh,et al.  Systemic Lidocaine Blocks Nerve Injury‐induced Hyperalgesia and Nociceptor‐driven Spinal Sensitization in the Rat , 1994, Anesthesiology.