Potent analgesic effects of anticonvulsants on peripheral thermal nociception in rats

Abstract

1 Anticonvulsant agents are commonly used to treat neuropathic pain conditions because of their effects on voltage-and ligand-gated channels in central pain pathways. However, their interaction with ion channels in peripheral pain pathways is poorly understood. Therefore, we studied the potential analgesic effects of commonly used anticonvulsant agents in peripheral nociception. 2 We injected anticonvulsants intradermally into peripheral receptive fields of sensory neurons in the hindpaws of adult rats, and studied pain perception using the model of acute thermal nociception. Commonly used anticonvulsants such as voltage-gated Na þ channel blockers, phenytoin and carbamazepine, and voltage-gated Ca 2 þ channel blockers, gabapentin and ethosuximide, induced dose-dependent analgesia in the injected paw, with ED 50 values of 0.30, 0.32 and 8, 410 mg per 100 ml, respectively. 3 Thermal nociceptive responses were not affected in the contralateral, noninjected paws, indicating a lack of systemic effects with doses of anticonvulsants that elicited local analgesia. 4 Hill slope coefficients for the tested anticonvulsants indicate that the dose -response curve was less steep for gabapentin than for phenytoin, carbamazepine and ethosuximide. 5 Our data strongly suggest that cellular targets like voltage-gated Na þ and Ca 2 þ channels, similar to those that mediate the effects of anticonvulsant agents in the CNS, may exist in the peripheral nerve endings of rat sensory neurons. Thus, peripherally applied anticonvulsants that block voltage-gated Na þ and Ca 2 þ channels may be useful analgesics.

Peripheral Antinociception by Carbamazepine in an Inflammatory Mechanical Hyperalgesia Model in the Rat: a New Target for Carbamazepine?

“…Recently, some authors demonstrated that carbamazepine injected intraplantarly into the rat hind paw is a potent analgesic against acute thermal nociception in rats (11). The doses of carbamazepine they used were 3,000 -6,000 times lower than the commonly used doses of lidocaine (1% -2% solution or 1 -2 mg/ 0.1 ml), a well known and widely used local anesthetic.…”

Analgesic Neuropeptide W Suppresses Seizures in the Brain Revealed by Rational Repositioning and Peptide Engineering

“…Price et al showed that direct injection of NPW-23 into the hypothalamus influenced the excitability of specific groups of neurons in rats (17,18). In short, NPW has been shown to be a multifunctional endogenous ligand for NPBW 1 (19). In this work, we tested the hypothesis that, based on its analgesic properties, NPW may also suppress seizures when delivered into the brain.…”

“…We hypothesize that the observed anticonvulsant effects exerted by hNPW-23, and the modified NPW analogues, resulted from activation of the NPBW 1 receptor which may result in hyperpolarization of the cell membrane. Hyperpolarization of the membrane would then result in decreased excitatory behavior of the neuron, thus modulating seizure activity (1,17). This hypothesis remains to be tested, and it is acknowledged that further studies into the precise mechanism by which NPW inhibits neuronal hyperexcitability need to be conducted.…”

“…The recent use of antiepileptic compounds for the treatment of pain (repositioning) is largely due to the compounds' ability to inhibit excessive firing in neurons through voltage and ligand-gated ion channel activities (1). It has been well documented that several anticonvulsant neuropeptides possess concurrent antiepileptic and analgesic activities (Supporting Information Table S1).…”

Pharmacotherapy of Neuropathic Pain

“…Anticonvulsant agents have been used in pain management over the last few decades due to the clinical impression that they are effective in alleviating certain forms of pain for example neuropathic pain especially lancinating and burning pain (Todorovic et al, 2003), cancer pain (Keskinbora et al, 2007). Gabapentin has attracted recent attention because of its effectiveness against neuropathic pain in both controlled clinical trials and animal models (Kayser and Christensen, 2000).…”