Antiallodynic Effect of Pregabalin in Rat Models of Sympathetically Maintained and Sympathetic Independent Neuropathic Pain

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Abstract

Pregabalin binds to the voltage-dependent calcium channel α2δ subunit and modulates the release of neurotransmitters, resulting in analgesic effects on neuropathic pain. Neuropathic pain has both sympathetically maintained pain (SMP) and sympathetic independent pain (SIP) components. We studied the antiallodynic effects of pregabalin on tactile allodynia (TA) and cold allodynia (CA) in SMP-and SIP-dominant neuropathic pain models. Allodynia was induced by ligation of the L5 & L6 spinal nerves (SMP model) or by transection of the tibial and sural nerves (SIP model) in rats. For intrathecal drug administration, a PE-10 catheter was implanted through the atlantooccipital membrane to the lumbar enlargement. Pregabalin was administered either intraperitoneally (IP) or intrathecally (IT) and dosed up incrementally until an antiallodynic effect without sedation or motor impairment was apparent. TA was assessed using von Frey filaments, and CA was assessed using acetone drops. IP-administered pregabalin dose-dependently attenuated TA in both models and CA in the SMP model, but not CA in the SIP model. IT-administered pregabalin dose-dependently attenuated both TA and CA in both models. However, the dose response curve of IT-administered pregabalin in SMP was shifted to left from that of SIP and the ED ₅₀ of IT-administered pregabalin for CA in SMP was about 900 times less than that in SIP. These findings suggest that pregabalin exerts its antiallodynic effect mainly by acting at the spinal cord, and that IT-administered pregabalin has more potent antiallodynic effects in SMP. The α2δ subunit might be less involved in the CA in SIP.

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An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat.

Paul Chung, K. Fan Chung, H. Kim (1992)

We attempted to develop an experimental animal model for peripheral neuropathic pain. Under sodium pentobarbital anesthesia, both the L5 and L6 spinal nerves (group 1) or the L5 spinal nerve alone (group 2) of one side of the rat were tightly ligated. For comparison, a parallel study was conducted with another group of rats (group 3) which received a partial tight sciatic nerve ligation, a paradigm developed previously as a neuropathy model. Withdrawal latencies to application of radiant heat to the foot were tested for the next 16 weeks in all 3 groups. Sensitivity of the hind paw to mechanical stimulation was tested with von Frey filaments. The general behavior of each rat was noted during the entire test period. Results suggested that the surgical procedure in all 3 groups produced a long-lasting hyperalgesia to noxious heat (at least 5 weeks) and mechanical allodynia (at least 10 weeks) of the affected foot. In addition, there were behavioral signs of the presence of spontaneous pain in the affected foot. Therefore, we believe we have developed an experimental animal model for peripheral neuropathy using tight ligations of spinal nerves. The model manifests the symptoms of human patients with causalgia and is compatible with a previously developed neuropathy model. The present model has two unique features. First, the surgical procedure is stereotyped. Second, the levels of injured and intact spinal segments are completely separated, allowing independent experimental manipulations of the injured and intact spinal segments in future experiments to answer questions regarding mechanisms underlying causalgia.

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Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia.

M Michaelis, M. Devor, W Jänig … (1993)

In humans, trauma to a peripheral nerve may be followed by chronic pain syndromes which are only relieved by blockade of the effects of sympathetic impulse traffic. It is presumed that, after the lesion, noradrenaline released by activity of sympathetic postganglionic axons excites primary afferent neurons by activating alpha-adrenoceptors, generating signals that enter the 'pain pathways' of the central nervous system. The site of coupling is unclear. In some patients local anaesthesia of the relevant peripheral nerve does not alleviate pain, implying that ectopic impulses arise either within the central nervous system, or in proximal parts of the primary afferent neurons. In experimentally lesioned rats, activity can originate within the dorsal root ganglia. Here we report that, after sciatic nerve ligation, noradrenergic perivascular axons in rats sprout into dorsal root ganglia and form basket-like structures around large-diameter axotomized sensory neurons; sympathetic stimulation can activate such neurons repetitively. These unusual connections provide a possible origin for abnormal discharge following peripheral nerve damage. Further, in contrast to the sprouting of intact nerve terminals into nearby denervated effector tissues in skin, muscle, sympathetic ganglia and sweat glands, the axons sprout into a target which has not been partially denervated.

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Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex.

Klaus G Fink, David Dooley, Wolfgang P. Meder … (2002)

Gabapentin and pregabalin (S-(+)-3-isobutylgaba) produced concentration-dependent inhibitions of the K(+)-induced [Ca(2+)](i) increase in fura-2-loaded human neocortical synaptosomes (IC(50)=17 microM for both compounds; respective maximal inhibitions of 37 and 35%). The weaker enantiomer of pregabalin, R-(-)-3-isobutylgaba, was inactive. These findings were consistent with the potency of these drugs to inhibit [(3)H]-gabapentin binding to human neocortical membranes. The inhibitory effect of gabapentin on the K(+)-induced [Ca(2+)](i) increase was prevented by the P/Q-type voltage-gated Ca(2+) channel blocker omega-agatoxin IVA. The alpha 2 delta-1, alpha 2 delta-2, and alpha 2 delta-3 subunits of voltage-gated Ca(2+) channels, presumed sites of gabapentin and pregabalin action, were detected with immunoblots of human neocortical synaptosomes. The K(+)-evoked release of [(3)H]-noradrenaline from human neocortical slices was inhibited by gabapentin (maximal inhibition of 31%); this effect was prevented by the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide). Gabapentin and pregabalin may bind to the Ca(2+) channel alpha 2 delta subunit to selectively attenuate depolarization-induced Ca(2+) influx of presynaptic P/Q-type Ca(2+) channels; this results in decreased glutamate/aspartate release from excitatory amino acid nerve terminals leading to a reduced activation of AMPA heteroreceptors on noradrenergic nerve terminals.

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Author and article information

Journal

Journal ID (nlm-ta): Yonsei Med J

Journal ID (publisher-id): YMJ

Title: Yonsei Medical Journal

Publisher: Yonsei University College of Medicine

ISSN (Print): 0513-5796

ISSN (Electronic): 1976-2437

Publication date (Print): 28 February 2007

Publication date (Electronic): 20 February 2007

Volume: 48

Issue: 1

Pages: 41-47

Affiliations

Department of Anesthesiology and Pain Medicine and Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea.

Author notes

Reprint address: requests to Dr. Youn-Woo Lee, Department of Anesthesiology and Pain Medicine and Anesthesia and Pain Research Institute, Yongdong Severance Hospital, Yonsei University College of Medicine, 146-92 Dogok-dong, Kangnam-gu, Seoul 135-720, Korea. Tel: 82-2-2019-3520, Fax: 82-2-3463-0940, ywleepain@ 123456yumc.yonsei.ac.kr

Article

DOI: 10.3349/ymj.2007.48.1.41

PMC ID: 2628009

PubMed ID: 17326244

SO-VID: 96f7e066-9072-428b-8aa9-8fb08c2a73aa

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Antiallodynic Effect of Pregabalin in Rat Models of Sympathetically Maintained and Sympathetic Independent Neuropathic Pain

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Most cited references 31

An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat.

Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia.

Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex.

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