(297) Central adenosine A3 receptor (A3AR) activation reverses neuropathic pain

Abstract

Neuropathic pain is a substantial socioeconomic burden. Management of individuals suffering with neuropathic pain is inadequate, thus, new therapeutic targets are needed. We have recently reported that selective activation of the adenosine subtype 3 receptor (A3AR) potently reverses and blocks evoked pain behaviors associated with preclinical models of nerve injury- (chronic constriction injury, CCI) and chemotherapy-induced neuropathic pain. Although these studies suggest a role for targeting A3AR activation to mitigate pain behaviors, the sites and mechanisms of action of A3AR agonists are unknown. Here we examined the central sites of action for a recently characterized highly selective A3AR agonist, MRS5698, in CCI- and chemotherapy- (oxaliplatin) induced neuropathic pain. Systemic injection of MRS5698 (0.1, 0.3, 1 mg/kg) dose dependently reversed CCI mechanical allodynia [n=5 per group; ED50 = 0.35 mg/kg (95%CI: 0.20-0.61)]. These effects were blocked by systemic administration of a highly selective A3AR antagonist, MRS1523 (2 mg/kg). MRS5698 (1 mg/kg; n=4) also reversed oxaliplatin-induced mechanical allodynia and hyperalgesia behaviors. The effects of systemic MRS5698 (1 mg/kg) in CCI and oxaliplatin rats were blocked by intrathecal or intra-rostral ventromedial medulla (RVM) injections of MRS1523 (1 nmol; n=4), suggesting important central mechanisms for the actions of MRS5698. Further examination demonstrated that A3AR activation following intra-RVM injection of MRS5698 (0.3, 1, 3 nmol; n=5) dose dependently reversed CCI-induced mechanical allodynia; an effect blocked by RVM injection of MRS1523 (1 nmol). This reduction in mechanical allodynia following intra-RVM A3AR activation (MRS5698, 3 nmol) was transiently reversed by intrathecal injection of the non-selective serotonergic receptor antagonist, methysergide (30 μg), or the noradrenergic α2 receptor antagonist, yohimbine (30 μg, n=5). Taken together, these experiments suggest the protective effects of A3AR agonists occur, in part, through A3AR activation in the spinal cord and RVM, which engages potent bulbospinal inhibitory pathways to reverse neuropathic pain of several etiologies. Neuropathic pain is a substantial socioeconomic burden. Management of individuals suffering with neuropathic pain is inadequate, thus, new therapeutic targets are needed. We have recently reported that selective activation of the adenosine subtype 3 receptor (A3AR) potently reverses and blocks evoked pain behaviors associated with preclinical models of nerve injury- (chronic constriction injury, CCI) and chemotherapy-induced neuropathic pain. Although these studies suggest a role for targeting A3AR activation to mitigate pain behaviors, the sites and mechanisms of action of A3AR agonists are unknown. Here we examined the central sites of action for a recently characterized highly selective A3AR agonist, MRS5698, in CCI- and chemotherapy- (oxaliplatin) induced neuropathic pain. Systemic injection of MRS5698 (0.1, 0.3, 1 mg/kg) dose dependently reversed CCI mechanical allodynia [n=5 per group; ED50 = 0.35 mg/kg (95%CI: 0.20-0.61)]. These effects were blocked by systemic administration of a highly selective A3AR antagonist, MRS1523 (2 mg/kg). MRS5698 (1 mg/kg; n=4) also reversed oxaliplatin-induced mechanical allodynia and hyperalgesia behaviors. The effects of systemic MRS5698 (1 mg/kg) in CCI and oxaliplatin rats were blocked by intrathecal or intra-rostral ventromedial medulla (RVM) injections of MRS1523 (1 nmol; n=4), suggesting important central mechanisms for the actions of MRS5698. Further examination demonstrated that A3AR activation following intra-RVM injection of MRS5698 (0.3, 1, 3 nmol; n=5) dose dependently reversed CCI-induced mechanical allodynia; an effect blocked by RVM injection of MRS1523 (1 nmol). This reduction in mechanical allodynia following intra-RVM A3AR activation (MRS5698, 3 nmol) was transiently reversed by intrathecal injection of the non-selective serotonergic receptor antagonist, methysergide (30 μg), or the noradrenergic α2 receptor antagonist, yohimbine (30 μg, n=5). Taken together, these experiments suggest the protective effects of A3AR agonists occur, in part, through A3AR activation in the spinal cord and RVM, which engages potent bulbospinal inhibitory pathways to reverse neuropathic pain of several etiologies.