Peripheral Mechanisms of Neuropathic Pain—The Role of Neuronal and Non-Neuronal Interactions and Their Implications for Topical Treatment of Neuropathic Pain

Abstract

Neuropathic pain in humans arises as a consequence of injury or disease of somatosensory nervous system at peripheral or central level. Peripheral neuropathic pain is more common than central neuropathic pain, and is supposed to result from peripheral mechanisms, following nerve injury. The animal models of neuropathic pain show extensive functional and structural changes occurring in neuronal and non-neuronal cells in response to peripheral nerve injury. These pathological changes following damage lead to peripheral sensitization development, and subsequently to central sensitization initiation with spinal and supraspinal mechanism involved. The aim of this narrative review paper is to discuss the mechanisms engaged in peripheral neuropathic pain generation and maintenance, with special focus on the role of glial, immune, and epithelial cells in peripheral nociception. Based on the preclinical and clinical studies, interactions between neuronal and non-neuronal cells have been described, pointing out at the molecular/cellular underlying mechanisms of neuropathic pain, which might be potentially targeted by topical treatments in clinical practice. The modulation of the complex neuro-immuno-cutaneous interactions in the periphery represents a strategy for the development of new topical analgesics and their utilization in clinical settings.

A Hydroethanolic Leaf Extract of Persicaria lanigera Possesses Antinociceptive Activity through Cytokine and Glutamatergic Pathways In Vivo

“…These receptors are normally implicated in nociceptive primary afferent transmissions and the development and maintenance of nociception [ 31 ]. The nociceptive behaviour evoked by glutamate occurs mainly in the peripheral, spinal, and supraspinal sites by interacting with N-methyl-D-aspartate (NMDA) and non-NMDA receptors [ 32 ]. Glutamate also induces the release of some inflammatory mediators such as nitric oxide (NO), prostaglandins, bradykinin, and NO-related substances [ 28 ].…”

Topical Treatments and Their Molecular/Cellular Mechanisms in Patients with Peripheral Neuropathic Pain—Narrative Review

“…The injury of peripheral neurons, independently of the cause and level of the damage, induces complex functional and structural changes not only in neurons (sensory and motor) and glial cells but also in non-neuronal cells such as keratinocytes and immunocompetent cells (e.g., macrophages, mast cells, neutrophils). The complex neuro-immune-cutaneous interactions, their changes observed after peripheral nerve injury, and their role in generation and maintenance of NP were reviewed in our paper published recently [10].…”

“…Although only a few molecular/cellular mechanisms of NP in humans are directly elucidated [10], the following preclinical and clinical findings justify the utilization of topical analgesics in clinical practice.…”

“…Some of them are also expressed by non-neuronal cells (Figure 1). Moreover, peripheral neurons interact closely via several signaling molecules with immunocompetent cells and keratinocytes and this interplay under pathological conditions is responsible for neuronal hyperexcitability and NP generation (Figure 1) [10,11]. These facts enable the development of pharmacotherapies specifically targeting peripheral mechanisms, e.g., topical analgesics.…”

Psoas Major Muscle Volume Does Not Affect the Postoperative Thigh Symptoms in XLIF Surgery

“…When approaching near the nerve plexus, a process of degenerative cellular and molecular changes due to injury of the nerve could occur, either from direct mechanical insult of the surgical approach or insertion of the instrument or from the reduction of blood supply and oxygen [5]. This leads to neuropathic pain, which could manifest as variety of symptoms such as pain associated with positive or negative sensory signs [6].…”