Research ReportPost-ictal analgesia in genetically epilepsy-prone rats is induced by audiogenic seizures and involves cannabinoid receptors in the periaqueductal gray
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.
ReferenceS (34)
- et al.
Opioid neurotransmission in the post-ictal analgesia: involvement of mu(1)-opioid receptor
Brain Res.
(2001) - et al.
Involvement of 5-HT(2) serotonergic receptors of the nucleus raphe magnus and nucleus reticularis gigantocellularis/paragigantocellularis complex neural networks in the antinociceptive phenomenon that follows the post-ictal immobility syndrome
Exp. Neurol.
(2006) - et al.
Serotonergic neurotransmission in the dorsal raphe nucleus recruits in situ 5-HT(2A/2C) receptors to modulate the post-ictal antinociception
Exp. Neurol.
(2008) - et al.
5-HT1A/1B, 5-HT6, and 5-HT7 serotonergic receptors recruitment in tonic-clonic seizure-induced antinociception: role of dorsal raphe nucleus
Exp. Neurol.
(2009) - et al.
Nociceptive threshold in patients with epilepsy
Epilepsy Res.
(1992) - et al.
A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia
Pain
(1988) - et al.
Neurotransmitter abnormalities as determinants of seizure susceptibility and intensity in the genetic models of epilepsy
Biochem. Pharmacol.
(1981) - et al.
Noradrenergic and serotonergic determinants of seizure susceptibility and severity in genetically epilepsy-prone rats
Life Sci.
(1986) - et al.
Analgesia from electrical stimulation of the periaqueductal gray matter in the cat: behavioral observations and inhibitory effects on spinal cord interneurons
Brain Res.
(1973) Analgesia produced by electrical stimulation of the brain
Prog. Neuropsychopharmacol. Biol. Psychiatry
(1984)
Focal injection of 2-amino-7-phosphonoheptanoic acid into prepiriform cortex protects against pilocarpine-induced limbic seizures in rats
Neurosci. Lett.
Evidence for GABA involvement in midbrain control of medullary neurons that modulate nociceptive transmission
Brain Res.
The periaqueductal grey is a critical site in the neuronal network for audiogenic seizures: modulation by GABA(A) NMDA and opioid receptors
Epilepsy Res.
Involvement of prolactin, vasopressin and opioids in post-ictal antinociception induced by electroshock in rats
Brain Res.
Identification of the requisite brain sites in the neuronal network subserving generalized clonic audiogenic seizures
Brain Res.
Inhibition of fatty-acid amide hydrolase enhances cannabinoid stress-induced analgesia: sites of action in the dorsolateral periaqueductal gray and rostral ventromedial medulla
Neuropharmacology
Localization of the antinociceptive and antianalgesic effects of neurotensin within the rostral ventromedial medulla
Neurosci. Lett.
Cited by (26)
Genetic models of audiogenic seizures: What they are and how cannabinoids and Cannabis-derived compounds can be used to alleviate their symptoms—An updated narrative
2023, Medicinal Usage of Cannabis and CannabinoidsVentrolateral Periaqueductal Gray Matter Neurochemical Lesion Facilitates Epileptogenesis and Enhances Pain Sensitivity in Epileptic Rats
2019, NeuroscienceCitation Excerpt :Thus, the impairment of vlPAG network due to cell loss and alterations of excitatory and inhibitory transmissions after SE induction may, in turn, enhance SRS. Studies have demonstrated the induction of post-ictal analgesia following electroshock or drug-induced seizures in rats (Urca et al., 1981; Coimbra et al., 2001; de Oliveira et al., 2006; Samineni et al., 2011). This phenomenon of post-ictal analgesia is also known to occur in human epilepsy (Guieu et al., 1992).
Does pain sensitivity increase during ictal period? Evidence from absence epileptic WAG/Rij rats
2018, Epilepsy and BehaviorCitation Excerpt :Analysis of interictal and ictal pain sensitivities may provide insights into shared neurobiological mechanisms underlying these comorbid disorders. There are several studies focused on pain sensitivity in epilepsy [9–18]. Most of them focused on pain sensitivity during the postictal period in animals [9–15].
Neurotoxic lesions of the pedunculopontine tegmental nucleus impair the elaboration of postictal antinociception
2018, Physiology and BehaviorEpilepsy may cause increased pain sensitivity: Evidence from absence epileptic WAG/Rij rats
2017, Epilepsy and Behavior