Chemokine CCL2 and its receptor CCR2 in the dorsal root ganglion contribute to oxaliplatin-induced mechanical hypersensitivity

Abstract

Activation of innate immune mechanisms within the dorsal root ganglion and spinal dorsal horn has been shown to play a key role in the development of neuropathic pain including paclitaxel-related chemotherapy-induced peripheral neuropathy (CIPN). Here, we tested whether similar mechanisms are generalizable to oxaliplatin-induced CIPN. After a single intraperitoneal injection of 3 mg/kg oxaliplatin, mechanical withdrawal threshold and the expression of C-C chemokine ligand 2 (CCL2) and its receptor, CCR2, in the dorsal root ganglion were measured by behavioral testing and immunohistochemical staining, respectively. Mechanical responsiveness increased from the first day after oxaliplatin injection and persisted until day 15, the last day of this experiment. Immunohistochemical showed that the expression of CCL2/CCR2 started to increase by 4 hours after oxaliplatin treatment, was significantly increased at day 4, and then both signals became normalized by day 15. Cotreatment with intrathecal anti-CCL2 antibodies prevented the development of oxaliplatin-induced mechanical hyperresponsiveness, and transiently reversed established hyperalgesia when given 1 week after chemotherapy. This is the first study to demonstrate CCL2/CCR2 signaling in a model of oxaliplatin-related CIPN; and it further shows that blocking of this signal can attenuate the development of oxaliplatin-induced mechanical hyperalgesia. Activation of innate immune mechanisms may therefore be a generalized basis for CIPN irrespective of the specific class of agent.

The blockade of CC chemokine receptor type 1 influences the level of nociceptive factors and enhances opioid analgesic potency in a rat model of neuropathic pain

“…Among these cytokines, CCL2, CCL4 and CCL7, like CCL3 and CCL6, seem to also be important for the maintenance of neuropathy, and higher levels were still noted on the 28th day post‐CCI. Importantly, there is evidence that the above‐mentioned chemokines are also up‐regulated in other models of neuropathic pain, such as partial sciatic nerve ligation, oxaliplatin‐induced mechanical hypersensitivity and paclitaxel‐induced mechanical allodynia . We observed that CCL5 remained unchanged at the spinal cord level and was down‐regulated in the DRG.…”

“…Importantly, there is evidence that the above-mentioned chemokines are also up-regulated in other models of neuropathic pain, such as partial sciatic nerve ligation, oxaliplatin-induced mechanical hypersensitivity and paclitaxel-induced mechanical allodynia. [46][47][48][49][50] We observed that CCL5 remained unchanged at the spinal cord level and was down-regulated in the DRG. Some previous studies have suggested that CCL5 up-regulation at the site of injury is a common determinant of neuropathic pain development.…”

Mild traumatic brain injury is associated with effect of inflammation on structural changes of default mode network in those developing chronic pain

“…Nevertheless, signi cant CCL2 rise over time and GM volume increase in dPCC were found in patients developing the CPTH, suggesting that the consistently observed associations of in ammation on PTH were at least partially attributable to their effect on GMV alternations. Taken together, the current study highlighted the role of the circulating CCL2 level in the pathogenesis and progression of PTH (48)(49)(50), and emphasized on the neuroin ammatory mechanism in morphological alternations associated with pain modulation in cognitive domain.…”

Isotalatizidine, a C19-diterpenoid alkaloid, attenuates chronic neuropathic pain through stimulating ERK/CREB signaling pathway-mediated microglial dynorphin A expression

“…However, persistent activation of the microglial cells can elevate neuronal excitability and maintain the transmission of pain signals to the spinal dorsal horn neurons [12,13]. Indeed, the basis of neuropathic pain is the production of proinflammatory and pro-nociceptive mediators such as interleukins (IL-1β, IL-6, IL-12, IL-15, IL-18) [14], IFN-γ, TNF-α [15], and chemokines (CCL2, CCL3, CCL4, CCL5, CCL7) [16,17] by the constitutively active microglia cells [12,18,19]. The mitogen-activated protein kinase (MAPKs) family of proteins, including extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), plays a crucial role in the signaling pathways mediating microglial activation and nociceptive responses, which eventually lead to neuropathic pain [20,21].…”