Exacerbation of tonic but not phasic pain by entorhinal cortex lesions

Highlights

• We performed medial (MEC), lateral (LEC) or sham entorhinal cortex lesions in rats.

• Neither MEC nor LEC lesions affected the hot plate test.

• Neither MEC nor LEC lesions affected the first phase of formalin test.

• MEC and LEC lesions increased paw licking in the second phase of formalin test.

Abstract

The hippocampus is actively involved in pain modulation. Previous studies have shown that inhibition, resection or pharmacological interference of the hippocampus or its subcortical afferent sources such as the medial septum and amygdala produce anti-nociceptive effects. But how the cortical connections of the hippocampus modulate pain remains unexplored. The entorhinal cortex (EC) constitutes the major gateway between the hippocampus and the neocortex. In the present study, rats with medial (MEC), lateral (LEC) or sham EC lesions and received the hot plate and the intra-plantar formalin injection tests. Neither MEC nor LEC lesions affected the hot plate test and the first phase of the formalin test. In contrast, paw licking responses in the second phase of the formalin test significantly increased with both MEC and LEC lesions. These results suggested that that the hippocampal–cortical interactions channeled by the EC were involved in tonic but not phasic pain conditions, and that cortical and sub-cortical connections of the hippocampus played independent roles in pain modulation.

Introduction

The hippocampus actively participates in pain processing and modulation. Hippocampal neurons respond to noxious stimuli [1], [2], whereas electrical stimulation of the hippocampal formation evokes painful sensations in humans [3]. Persistent pain in adult [4], [5], [6] and neonatal rodents [7], [8], [9] changes hippocampal morphology, electrophysiology and function, and affects its neurogenesis. Inhibition [10], resection [11] or pharmacological interference [12], [13], [14], [15], [16] of the hippocampus modulates formalin-induced pain behaviors.

Evidence suggests that the hippocampus plays distinct roles under different pain conditions. For example, hippocampal inhibition attenuates tonic pain induced by formalin injection [10], [12], [13], but no differences of phasic pain in the hot plate or tail flick tests are detected with hippocampal lesions [17]. The underlying mechanisms remain unclear, partly because of its complicated anatomy. Medial septum, amygdala, thalamus and hypothalamus send subcortical afferents to the hippocampus whereas its cortical connections almost exclusively pass through the entorhinal cortex (EC). Cortical information enters the hippocampus through layers II/III of the EC, and after processing, returns to these regions through EC deep layers. The EC can be further subdivided, on both anatomical and functional basis, into medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC), which process spatial and nonspatial information, respectively [18], [19], [20].

The pain-modulatory effects of subcortical afferents of the hippocampus have been demonstrated by studies showing that inhibition, resection or stimulation of the medial septum [21], [22], amygdala [23], [24], [25] and hypothalamus [26], [27] alter pain behaviors. However, whether and how cortical connections of the hippocampus modulate pain remains unexplored. The present study aims to examine how EC lesions, which disrupt the hippocampal–cortical gateway, affect phasic and tonic pain conditions.