Abstract
Neuropathic pain (NP) remains an untreatable disease due to the complex pathophysiology that involves the whole pain neuraxis including the forebrain. Sensory dysfunctions such as allodynia and hyperalgesia are only part of the symptoms associated with neuropathic pain that extend to memory and affectivity deficits. The development of multi-target molecules might be a promising therapeutic strategy against the symptoms associated with NP. 2-pentadecyl-2-oxazoline (PEA-OXA) is a plant-derived agent, which has shown effectiveness against chronic pain and associated neuropsychiatric disorders. The molecular mechanisms by which PEA-OXA exerts its effects are, however, only partially known. In the current study, we show that PEA-OXA, besides being an alpha2 adrenergic receptor antagonist, also acts as a modulator at histamine H3 receptors, and report data on its effects on sensory, affective and cognitive symptoms associated with the spared nerve injury (SNI) model of neuropathic pain in mice. Treatment for 14 days with PEA-OXA after the onset of the symptoms associated with neuropathic pain resulted in the following effects: (i) allodynia was decreased; (ii) affective/cognitive impairment associated with SNI (depression, spatial, and working memories) was counteracted; (iii) long-term potentiation in vivo in the lateral entorhinal cortex-dentate gyrus (perforant pathway, LPP) was ameliorated, (iv) hippocampal glutamate, GABA, histamine, norepinephrine and dopamine altered levels after peripheral nerve injury were reversed, (v) expression level of the TH positive neurons in the Locus Coeruleus were normalized. Thus, a 16-day treatment with PEA-OXA alleviates the sensory, emotional, cognitive, electrophysiological and neurochemical alterations associated with SNI-induced neuropathic pain.
Highlights
The entorhinal cortex-hippocampus pathway plays a pivotal role in persistent pain such that cortical projections to the hippocampus can differently affect pain perception [12, 13] The interactions between the lateral entorhinal cortex (LEC) and the dentate gyrus (DG) are in charge with the integration of important emotional stimuli associated with space–time orientation and place memory storage [14]
Once that its pharmacological activity at the histamine H3 receptor was demonstrated for the first time, we evaluated the effect of repeated administrations (16 days starting the treatment 14 days after sciatic nerve surgery) of PEA-OXA on: (i) mechanical allodynia, (ii) affective and cognitive behavior, (iii) neural activity in the locus coeruleus (LC), (iv) in vivo long term potentiation in the entorhinal-cortex/dentate gyrus, LPP, and (iv) glutamate, GABA, norepinephrine, dopamine and histamine levels in the hippocampus
Homology modelling of histamine H3 receptor The sequences of the histamine H3 receptor was retrieved from the publicly available sequence database www.uniprot.org (UNIPROT: Q9Y5N1). 50 homology models of receptor were built with MODELLER [32, 33] version 9.14 using the x-ray structure of the acetylcholine M 3 receptor (PDB id: 4U15) as a template and the structural alignment
Summary
In the last two decades, many investigations have been focused towards plastic changes at supra-spinal cortical [1,2,3] and non-cortical structures [4, 5] underlying cognitive/affective consequences of neuropathic pain.Boccella et al Mol Brain (2021) 14:28 the influence of neuropathic pain on hippocampal structures began to be studied many decades ago [6], only recently it has become the subject of more in-depth studies by several laboratories [7,8,9,10] The involvement of the hippocampus in spatial memory disorders and other comorbidities of neuropathic pain was recently shown in the spared nerve injury (SNI) model of neuropathic pain [7]. In the last two decades, many investigations have been focused towards plastic changes at supra-spinal cortical [1,2,3] and non-cortical structures [4, 5] underlying cognitive/affective consequences of neuropathic pain. Histamine H3 receptor blockade has been shown to relieve neuropathic pain [25, 26], the role of this receptor and the mechanisms underlying its supraspinal effects on the various components of neuropathic pain are still poorly understood. The evidence that the analgesic effects of H3 receptor antagonists/inverse agonists in neuropathic pain can be partially mediated by α2 adrenoceptor desensitization [23] inspired us to evaluate possible anti-neuropathic properties of PEA-OXA and investigate the possible involvement of H3 receptor
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