Spinal Dynorphin and Bradykinin Receptors Maintain Inflammatory Hyperalgesia

Abstract

An upregulation of the endogenous opioid, dynorphin A, in the spinal cord is seen in multiple experimental models of chronic pain. Recent findings implicate a direct excitatory action of dynorphin A at bradykinin receptors to promote hyperalgesia in nerve injured rats, and its upregulation may promote, rather than counteract, enhanced nociceptive input due to injury. Here we examined a model of inflammatory pain by unilateral injection of Complete Freund's Adjuvant (CFA) into the rat hind paw. Rats exhibited tactile hypersensitivity and thermal hyperalgesia in the inflamed paw by 6 hr after CFA injection, while a significant elevation of prodynorphin transcripts in the lumbar spinal cord was seen at day 3 but not at 6 hr. Thermal hyperalgesia at day 3, but not at 6 hr, after CFA injection was blocked by intrathecal administration of anti-dynorphin antiserum or by bradykinin receptor antagonists. The antihyperalgesic effect of the latter was not due to de novo production of bradykinin or upregulation of spinal bradykinin receptors. These data suggest that elevated spinal dynorphin upon peripheral inflammation mediates chronic inflammatory hyperalgesia. The antihyperalgesic effect of bradykinin receptor antagonists requires the presence of upregulated spinal dynorphin but not of de novo production of bradykinin, supporting our hypothesis that pathological levels of dynorphin may activate spinal bradykinin receptors to mediate inflammatory hyperalgesia.Perspective-This study shows that chronic peripheral inflammation induces a significant upregulation of the endogenous opioid peptide dynorphin. Elevated levels of spinal dynorphin and activation of spinal bradykinin receptors are essential to maintain inflammatory hyperalgesia. The results suggest that blockade of spinal bradykinin receptors may have therapeutic potential in chronic inflammatory pain.

Dynorphin a Analogs for the Treatment of Chronic Neuropathic Pain

“…The administration of a Dyn A antiserum to nerve-injured rats reversed the neuropathic pain state [80]. Similar results were seen in an inflammatory pain model, thus giving more evidence that the higher levels of Dyn A contribute to different pain states [91]. All of these data have led to the hypothesis that during chronic pain states there is an upregulation of Dyn A which results in pronociceptive effects through a nonopioid mechanism to maintain the pain state.…”

Sustainability and Clinical Effectiveness of Inpatient Rehabilitation in Painful Shoulder Diseases

“…ß-Endorphin release tends to result in pain relief as could be observed in physical therapy which leads to endorphin-induced analgesia [8]. Dynorphin is an endorphin that autoregulatory counter-regulates pain [10]. In case of a noxa the intracellular Ca 2+ increase inhibits the binding of DREAM (Downstream Regulatory Element Antagonist Modulator) whereby dynorphin binds and activates the opioid receptor.…”

Structure Activity Relationship of Stable Dynorphin A-(2-13) Analogues Interacting at the Bradykinin-2 Receptor

“…However, these fragments are biologically active both in vitro and in vivo, and being neuroexcitatory and neurotoxic, suggest a non-opioid pathway. These des-tyrosyl fragments of Dyn A have been found to bind to the bradykinin 2 receptor (B2R) and cause an influx of calcium [3]. In a chronic pain model, Dyn A was found to be up-regulated and contributes to the maintenance of neuropathic pain [3,4].…”

“…These des-tyrosyl fragments of Dyn A have been found to bind to the bradykinin 2 receptor (B2R) and cause an influx of calcium [3]. In a chronic pain model, Dyn A was found to be up-regulated and contributes to the maintenance of neuropathic pain [3,4]. Therefore, the development of B2R antagonists can be used to block the agonist actions of Dyn A which may lead to therapeutics for chronic pain.…”