Clonidine, an alpha‐2 adrenoceptor agonist relieves mechanical allodynia in oxaliplatin‐induced neuropathic mice; potentiation by spinal p38 MAPK inhibition without motor dysfunction and hypotension

Abstract

Cancer chemotherapy with platinum-based antineoplastic agents including oxaliplatin frequently results in a debilitating and painful peripheral neuropathy. We evaluated the antinociceptive effects of the alpha-2 adrenoceptor agonist, clonidine on oxaliplatin-induced neuropathic pain. Specifically, we determined if (i) the intraperitoneal (i.p.) injection of clonidine reduces mechanical allodynia in mice with an oxaliplatin-induced neuropathy and (ii) concurrent inhibition of p38 mitogen-activated protein kinase (MAPK) activity by the p38 MAPK inhibitor SB203580 enhances clonidine's antiallodynic effect. Clonidine (0.01-0.1 mg kg 21, i.p.), with or without SB203580(1-10 nmol, intrathecal) was administered two weeks after oxaliplatin injection(10 mg kg 21, i.p.) to mice. Mechanical withdrawal threshold, motor coordination and blood pressure were measured. Postmortem expression of p38 MAPK and ERK as well as their phosphorylated forms(p-p38 and p-ERK) were quantified 30 min or 4 hr after drug injection in the spinal cord dorsal horn of treated and control mice. Clonidine dose-dependently reduced oxaliplatininduced mechanical allodynia and spinal p-p38 MAPK expression, but not p-ERK. At 0.1 mg kg 21, clonidine also impaired motor coordination and decreased blood pressure. A 10 nmol dose of SB203580 alone significantly reduced mechanical allodynia and p-p38 MAPK expression, while a subeffective dose(3 nmol) potentiated the antiallodynic effect of 0.03 mg kg 21 clonidine and reduced the increased p-p38 MAPK. Coadministration of SB203580 and 0.03 mg kg 21 clonidine decreased allodynia similar to that of 0.10 mg kg 21 clonidine, but without significant motor or vascular effects. These findings demonstrate that clonidine treatment reduces oxaliplatin-induced mechanical allodynia. The concurrent administration of SB203580 reduces the dosage requirements for clonidine, thereby alleviating allodynia without producing undesirable motor or cardiovascular effects.Neuropathy is observed after application of various chemotherapy agents including paclitaxel, vincristine and cisplatin, 1,2 and presents as a mildly disrupting tingling sensation to an extremely painful paresthesia. 3 These dose-limiting side effects of chemotherapy treatments are much more disruptive and persistent, in comparison to other common side effects such as alopecia, emesis, diarrhea and fatigue. 4 Oxaliplatin is a third-generation platinum-based compound used as the primary therapy for metastatic colorectal cancer and other malignancies including lung, breast and ovarian cancer. 5-7Oxaliplatin can also induce prominent neuropathic pain that is characterized by pronounced cold and mechanical hypersensitivity and spontaneous pain. [8][9][10] Several types of analgesics, anticonvulsants and antioxidants that are approved for the treatment of other neuropathic pain states have shown little or no analgesic effect on chemotherapy-induced peripheral neuropathic pain in large randomized, placebo-controlled clinical trials. 11,12 Thus, it is of critical importance ...

Calcitonin gene-related peptide contributes to peripheral nerve injury-induced mechanical hypersensitivity through CCL5 and p38 pathways

“…Inhibition of CCL5 and CCL2 together, or blocking CCL2 while treating with a CGRP antagonist would be more effective in providing pain relief than inhibiting any one of these molecules alone. Further, the potential synergistic effects between individual treatments may help to reduce the side effects from each treatment alone, which has been shown when the combination treatment with clonidine (an alpha-2 adrenoceptor agonist) and p38 MAPK inhibition were used in an oxaliplatin-induced neuropathic pain model (Yeo et al, 2016). In summary, potential effective treatment for neuropathic pain should target multiple pro-nociceptive mediators and ideally, in order to reduce the side effects, should be known to specifically affect the injury or disease-induced function of these mediators.…”

Spinal α2‐adrenoceptors and neuropathic pain modulation; therapeutic target

“…injection of clonidine reduces mechanical allodynia in oxaliplatin‐induced neuropathic mice. Oxaliplatin is a platinum‐based agent, used as a therapy for cancer patients, which can also induce neuropathic pain (Yeo et al, ). Additionally, i.t.…”

“…Oxaliplatin is a platinum-based agent, used as a therapy for cancer patients, which can also induce neuropathic pain (Yeo et al, 2016).…”

“…In addition to changes of pre or postsynaptic ion channel conductance, the α 2 -adrenoceptors' activity can also influence the expression and activity of several neurotransmitters, receptors, and proteins. For example, Yeo et al (2016) noted that the antiallodynic effect of clonidine might be related to inhibiting phosphorylated p38 MAPK induced by oxaliplatin. Spinal phosphorylated p38 MAPK plays an important role in the induction and maintenance of neuropathic pain (Morioka, Tanabe, Inoue, Dohi, & Nakata, 2009).…”

Differential Development of Facial and Hind Paw Allodynia in a Nitroglycerin-Induced Mouse Model of Chronic Migraine: Role of Capsaicin Sensitive Primary Afferents

“…All experiments were performed blinded to the pharmacological treatment of the mice. 19) In order to examine whether TRPV1 expressing sensory nerve fibers are involved in the development of NTG-induced hypersensitivity, resiniferatoxin (RTX, LC Laboratory, Woburn, MA, U.S.A.; 0.02 mg/kg), was injected subcutaneously into the scruff of the neck 5 d before the first NTG injection. The chemical RTX, an ultrapotent synthetic TRPV1 agonist with significant initial transient hyperalgesia, induces the long-term desensitization of TRPV1 when administered systemically and then is able to deplete CSPAs of A-δ and C fiber sensory neurons in adult mice.…”