High-efficacy 5-HT1A receptor activation causes a curative-like action on allodynia in rats with spinal cord injury

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Abstract

The selective, high-efficacy 5-HT1A receptor agonist, (3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]-methanone (F 13640) has been reported to produce long-term analgesia in rodent models of chronic nociceptive and neuropathic pain; it also preempts allodynia following spinal cord injury. Here, rats underwent spinal cord injury, fully developed allodynia, and were infused with saline or 0.63 mg/day of F 13640 for 56 days. Infusion was then discontinued, and further assessments of allodynia (vocalization threshold to von Frey filament stimulation, responses to brush and cold) were conducted for another 70 days. F 13640-induced analgesia persisted during this post-treatment period. The data offer initial evidence that high-efficacy 5-HT1A receptor activation produces an unprecedented curative-like action on pathological pain.

Introduction

The recently discovered centrally-acting, broad-spectrum analgesic, F 13640, demonstrates high affinity for 5-HT1A receptors and activates those receptors to an extent that is unique among selective 5-HT1A receptor ligands (Colpaert et al., 2002). These molecular features make F 13640 induce novel neuroadaptive mechanisms whereby, in rodents, can be achieved an analgesia that grows rather than decays with chronicity and that is enhanced by the presence of nociceptive input. With chronic as well as acute nociceptive pains, these mechanisms cause an analgesia that is rivaled only by opioids (Colpaert et al., 2002, Bardin et al., 2003). With chronic neuropathic pains, continuous F 13640 infusion causes inverse tolerance and, hence, a lasting analgesia that cannot be achieved with opioids or analgesics exemplifying other molecular mechanisms of central action (Colpaert et al., 2002).

Current concepts distinguish between two, overlapping, types of pain (Ji and Woolf, 2001, Melzack et al., 2001). Physiological (e.g., nociceptive) pain refers to transient sensations that occur in response to noxious stimulation; the sensory apparatus bears similarity with other physiological sensations and produces a sensation that has adaptive significance. Pathological (e.g., neuropathic) pain develops progressively following nerve injury and loss of sensory input (Jensen, 2002); it may persist for a long time and is maladaptive (Ji and Woolf, 2001, Bruce et al., 2002, Siddall et al., 2002).

In a model of spinal cord injury-induced, central neuropathic pain, rats sustain a photochemical, ischaemic lesion of spinal cord dorsal horn segments L3–L5 and develop allodynic responses to cutaneous stimulations such as von Frey filament application, a gentle brush, or a cold spray (Hao et al., 1998). In this model, F 13640 infusion causes analgesia in a classic or “symptomatic” manner, alleviating these responses while the agent is being administered. Remarkably, the agent produces this analgesia in an incremental fashion, thus demonstrating inverse tolerance (Colpaert et al., 2002; see also Deseure et al., 2003). The infusion of morphine and of other agents exemplifying further molecular mechanisms of central analgesia (i.e., imipramine, ketamine, gabapentin) was ineffective (Colpaert et al., 2002). Equally remarkably, F 13640 “preempts” spinal cord injury-induced allodynia; F 13640 infusion from the time of injury onward inhibits the development of allodynia and allodynia remains at this reduced level upon the discontinuation of infusion (Wu et al., 2003; see also Deseure et al., 2003). Here, we determined whether in addition to its symptomatic and preemptive actions, F 13640 can also produce a “curative-like” action on spinal cord injury-induced neuropathic pain. In particular, spinal injured rats that had fully developed allodynia were infused with F 13640 or saline; we determined whether in these conditions F 13640's analgesic action would persist upon the discontinuation of F 13640 infusion.

Section snippets

Study design

In general conditions that have been detailed elsewhere (Wu et al., 2003), 32 female Sprague–Dawley rats (180–210 g; B&K Universal, Sollentuna, Sweden) underwent spinal cord injury and their responses to sensory stimulation were determined once weekly (see below). Four weeks after injury, 20 rats having demonstrated marked allodynia-like responses were selected for the study and assigned randomly to one of two groups (n=10/group) that were to be treated with either F 13640 or saline. For this,

Results

Repeated-measurement, two-factor analysis of variance (ANOVA; followed where appropriate by Fisher contrast analysis; Myers and Well, 1995; alpha=0.05) of data (Fig. 1) obtained during treatment indicated a significant effect of F 13640 with the von Frey threshold as well as with responses to brush and cold [F(1,15)=5.72, 6.29 and 7.78, respectively; P<0.05 in either case]. The effect of time was significant with brush and cold [F(15,240)=2.49; P<0.01 and F=1.74; P<0.05, respectively], but not

Discussion

The present data indicate that following F 13640 infusion in spinal cord-injured rats in which allodynia had been well established, analgesia persists for 10 weeks after the infusion was discontinued. This persistent analgesia is unlikely to be due to a persistent, molecular drug action; F 13640 was undetectable in arterial plasma 5 days after pump explantation. Also, the injection of the selective 5-HT1A receptor antagonist (N-4{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)

Acknowledgements

The authors thank E. Carilla-Durand for data management, S. Bréand for statistical analyses and C. Catala for preparing the paper.

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