GABAA but not GABAB receptors in the rostral anterior cingulate cortex selectively modulate pain-induced escape/avoidance behavior

Abstract

The rostral anterior cingulate cortex (rACC) is involved in supraspinal nociceptive processing. ACC lesions relieve persistent pain, but do not affect the patient's ability to localize a noxious stimulus. Since the rACC has a high density of GABA receptors, it is possible that pain processing is influenced by these receptors in the rACC. The present experiments examined the involvement of rat rACC GABA A and GABA B receptors in regard to sensitivity to mechanical stimulation and escape/ avoidance behavior in response to a noxious stimulus following L5 spinal nerve ligation. Rats were or were not afflicted with a neuropathic pain condition by an L5 spinal nerve ligation. rACC microinjection of 10 μg/μl GABA, a GABA A agonist (0.001 μg/μl, 0.1 μg/μl, or 0.5 μg/μl muscimol), a GABA B agonist (0.1 μg/μl, 1 μg/μl, or 5 μg/μl baclofen), or saline, did not alter mechanical withdrawal thresholds. Importantly, following 10 μg/μl GABA, 0.1 μg/μl, or 0.5 μg/μl muscimol microinjected into the rACC, place escape/avoidance behavior to a noxious mechanical stimulus was attenuated in injured animals. The attenuation was specific to the rACC and was blocked by a preadministered microinjection of the appropriate antagonist(s) into the rACC. In conclusion, microinjection of GABA and higher doses of muscimol did not decrease mechanical hyperalgesia but did attenuate place escape/avoidance behavior that is associated with mechanical stimulation of the ligated paw. These results provide additional support for the role of the rACC in higher order supraspinal processing of noxious events and suggest that rACC GABA A receptors significantly contribute to this processing. KeywordsGABA; Limbic System; Nociception; Escape; Avoidance; Cingulate Cortex Chronic pain conditions affect the lives of millions of individuals every day. Pain is considered to include sensory/discriminative, motivational/affective, and cognitive/evaluative dimensions (Melzack and Casey, 1968). Spinal and supraspinal mechanisms underlying the sensory dimension of pain have received much attention, while the underlying mechanisms of the Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptExp Neurol. Author manuscript; available in PMC 2008 March 1. Published in final edited form as:Exp Neurol. 2007 March ; 204(1): 182-194. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript affective dimension of pain remain unclear. Many structures in the limbic system are involved in affective drives and escape behavior. As a result, these brain regions may be involved in behavior re...

Comparison of the Novel Subtype-Selective GABAA Receptor-Positive Allosteric Modulator NS11394 [3′-[5-(1-Hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile] with Diazepam, Zolpidem, Bretazenil, and Gaboxadol in Rat Models of Inflammatory and Neuropathic Pain

“…However, other studies have shown that activation of GABA A receptors in the amygdala or the anterior cingulate cortex reverses both sensory and affective pain-like behaviors in neuropathic rats (LaGraize and Fuchs, 2007;Pedersen et al, 2007). In addition, preliminary work in our laboratory suggests that supraspinal mechanisms might also be relevant to antinociceptive actions of NS11394.…”

Role of Prelimbic GABAergic Circuits in Sensory and Emotional Aspects of Neuropathic Pain

“…A distinction between effects on emotional aspects of pain and learning and memory is a challenge with currently available paradigms for measuring emotional pain (Tappe-Theodor and Kuner, 2014). To address this issue, we used a place escape/avoidance (PEA) paradigm as an additional measure of emotional aspects of pain processing (LaBuda and Fuchs, 2000;LaGraize and Fuchs, 2007). The most parsimonious explanation for the observed PEA behavior is that it arises from aversion to the stimulation paradigm.…”

“…Parvalbumin-positive GABAergic basket cells synapse onto the somata and proximal dendrites of pyramidal cells, and their perisomatic inhibition regulates spike timing and synchronization of large populations of pyramidal cells. GABAergic modulation of pain transmission has been extensively investigated in the spinal cord, but its modulatory effect at the supraspinal level is only emerging (Gross et al, 2007;Hauck et al, 2007;LaGraize and Fuchs, 2007;Narita et al, 2011). Here, we used optogenetic approaches in conjunction with a spared nerve injury neuropathy model to investigate the role of parvalbumin (PV)-positive interneurons (PVINs) in pain modulation.…”

Behavioral assessments of the aversive quality of pain in animals

“…After electrical stimulation of nerve-injured rats, the aversive quality of noxious cutaneous hindpaw stimulation was attenuated [7] . It has also been found that GABA A but not GABA B receptors in the rostral ACC selectively modulate pain-induced escape/avoidance behavior [7,42] . In short, the PEAP can be used in neuropathic pain models and complete Freund's adjuvant inflammatory model [37][38][39][40][41]43] .…”

“…Freund's adjuvant models [9][10][11][12][13]27,28,[30][31][32]44] Modified CPA coupled with novel Neuropathic pain models and carrageenan Test pain-related affection under neuropathic objects paradigm inflammatory model [35] pain and inflammatory pain states Place escape/aversion paradigm Neuropathic pain models and complete Freund's Test pain-related affection under neuropathic adjuvant inflammatory model [37][38][39][40][41][42] pain and inflammatory pain states OPA: conditioned place avoidance. F-CPA: formalin-induced conditioned place avoidance.…”