Elsevier

Brain Research

Volume 1389, 10 May 2011, Pages 177-182
Brain Research

Research Report
Post-ictal analgesia in genetically epilepsy-prone rats is induced by audiogenic seizures and involves cannabinoid receptors in the periaqueductal gray

https://doi.org/10.1016/j.brainres.2011.03.041Get rights and content

Abstract

Post-ictal depression of consciousness occurs after generalized convulsive seizures, and includes analgesia, lasting for hours after electrically or chemically induced seizures in animals. The brain sites and mechanisms, mediating post-ictal analgesia, are unclear. The ventrolateral periaqueductal gray (PAG) is an important neuronal network site for mediating analgesia and also in generalized seizures, particularly in genetically epilepsy-prone rats (GEPRs). Endocannabinoids are implicated in mediating analgesia in several brain sites, including the PAG, and generalized seizures result in endocannabinoid release. This study evaluated if post-ictal analgesia occurs in GEPRs, following audiogenic seizures (AGS), and whether this analgesia involves endocannabinoid actions in PAG. Analgesia was evaluated, using thermal stimulation to evoke nociception, measuring changes in paw withdrawal latencies (PWLs) induced by AGS. Endocannabinoid involvement in post-ictal analgesia in GEPRs was evaluated, using focal bilateral microinjection of a cannabinoid (CB1) receptor antagonist (AM251) into PAG. AGS induced a significant increase in PWLs, lasting for ≥ 120 min. Microinjection of AM251 (100 and 200, but not 50 pmol/side) into PAG significantly decreased post-ictal analgesia in GEPRs. Endocannabinoids are also known to activate transient receptor potential vanilloid (TRPV1) receptors, but PAG microinjection of a TRPV1 receptor antagonist (capsazepine) did not affect post-ictal analgesia in GEPRs. These results indicate that AGS in GEPRs induce post-ictal analgesia, which is the first observation of this phenomenon in a genetic epilepsy model. These findings suggest an important role of PAG in post-ictal analgesia. The results also suggest that CB1 receptors in PAG are critical for mediating post-ictal analgesia in GEPRs.

Research Highlights

► Audiogenic seizures (AGS) induce post-ictal analgesia (PIA) in GEPRs. ► AGS-induced post-ictal analgesia lasted for ≥ 120 min after seizure. ► The periaqueductal gray (PAG) is critical for PIA in GEPRs. ► Microinjection of a CB1 antagonist into PAG blocked PIA in GEPRs. ► This is the first observation of post-ictal analgesia in a genetic form of epilepsy.

Introduction

Several studies have demonstrated that post-ictal analgesia is induced, following electroshock or drug-induced generalized seizures in rats (Coimbra et al., 2001, De Oliveira et al., 2006, Portugal-Santana et al., 2004, Urca et al., 1981). Reduced responsiveness to pain is also known to occur in certain forms of human epilepsy (Guieu et al., 1992). Genetically epilepsy-prone rats (GEPRs) are an inherited model of epilepsy that exhibits generalized tonic–clonic seizures in response to high intensity acoustic stimuli (Jobe and Laird, 1981). Previous studies have also shown that GEPRs exhibit greater susceptibility than normal rats to seizures induced by convulsant drugs, kindling, electroshock and hyperthermia, and GEPRs of the substrain GEPR-9 are also susceptible to severe audiogenic seizures (AGS) (Consroe and Edmonds, 1979, Faingold, 1999, Jobe et al., 1986).

The ventrolateral periaqueductal gray (PAG) is known to be a major nucleus in the network that mediates analgesia (Arvidsson et al., 1995) as well as generalized seizures, particularly in GEPRs (N'Gouemo and Faingold, 1999, Raisinghani and Faingold, 2003, Yang et al., 2003). Electrical stimulation of PAG is known to induce analgesia both in humans and animals (Mayer, 1984, Reynolds, 1969). The PAG plays a key role in the descending modulation of nociception by projecting via the rostral ventromedial medulla to spinal cord dorsal horn neurons (Liebeskind et al., 1973, Moreau and Fields, 1986, Urban and Smith, 1994).

Previous studies have suggested that the PAG is also an important site for endocannabinoid-mediated analgesia (Hohmann et al., 2005, Maione et al., 2006). Endocannabinoids, such as anandamide and 2-arachidonoyl glycerol, are lipid neuromodulators in the brain and activate cannabinoid (CB1 and CB2) receptors, which both modulate nociception. Endocannabinoids are also known to activate transient receptor potential vanilloid (TRPV1) receptors and to exert analgesic effects. Endocannabinoids are released, following seizure induction in rats (Wallace et al., 2001, Wallace et al., 2002, Wallace et al., 2003). Recent data also indicate that cannabinoid CB1 receptors are expressed in the PAG and may play a role in analgesia (Maione et al., 2006). We evaluated if induction of audiogenic seizures (AGS) in GEPRs would induce post-ictal analgesia. We also examined whether blockade of CB1 receptors or TRPV1 receptors by focal microinjection of a CB1 antagonist or TRPV1 antagonist into the PAG would inhibit any analgesic effects that occurred post-ictally in GEPRs.

Section snippets

Results

GEPRs showed a significant increase in PWLs after AGS induction as compared to pre-seizure baseline and compared to the PWLs 24 h later (Fig. 1). The increase in PWLs observed post-ictally was significant at 15, 30, 60 and 120 min after AGS (p < 0.05, one-way ANOVA). The analgesic effect was no longer present by 180 min in all GEPRs. Audiogenic seizure severity is evaluated using the scale of Jobe (Dailey and Jobe, 1985) wherein a score of 3 denotes generalized clonus, a score of 5 denotes hind limb

Discussion

The current results indicate that AGS induction in the GEPRs leads to post-ictal analgesia. The analgesic response observed after seizures was not affected by seizure severity. Thus, the GEPRs that exhibited seizures ending in generalized clonus, complete tonic extension or tonic hind limb extension, which are differing degrees of seizure severity according to the established AGS severity scale (Jobe et al., 1986), all showed a similar degree and duration of post-ictal analgesia. Although all

Animals

Twenty-four GEPRs (250–450 g, 6 males and 18 females) from the severe seizure strain (GEPR-9s) were screened for consistent AGS susceptibility at three weekly intervals according to established screening procedures (Dailey and Jobe, 1985). GEPRs used in the study were bred in the animal care facility of Southern Illinois University School of Medicine. Male Sprague–Dawley (SD) rats (250–350 g; Harlan Laboratories) were also utilized in this study. The experimental protocol used in this study

Acknowledgments

The authors wish to thank Marcus Randall for technical assistance, Stephen Verhulst, Ph.D. for statistical assistance and Diana Smith and Trish Ellis for manuscript assistance. This work was supported by grants from National Institutes of Health (NS042296 and DK065742) and EAM award from SIUSOM.

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