The Emerging Role of Spinal Dynorphin in Chronic Pain: A Therapeutic Perspective

Abstract

Notable findings point to the significance of the dynorphin peptide neurotransmitter in chronic pain. Spinal dynorphin neuropeptide levels are elevated during development of chronic pain. Importantly, knockout of the dynorphin gene prevents development of chronic pain in mice, but acute nociception is unaffected. Intrathecal (IT) administration of opioid and non-opioid dynorphin peptides initiate allodynia through a non-opioid receptor mechanism; furthermore, anti-dynorphin antibodies administered by the IT route attenuate chronic pain. Thus, this review presents the compelling evidence in the field supporting the role of dynorphin in facilitating the development of a persistent pain state. These observations raise the question of the control mechanisms responsible for the upregulation of spinal dynorphin leading to chronic pain development. Also, spinal dynorphin regulation of downstream signaling molecules may be implicated in hyperpathic states. Therapeutic strategies to reduce spinal dynorphin may provide a non-addictive approach to improve the devastating condition of chronic pain that occurs in numerous human diseases.

Preventive and alleviative effects of the dual enkephalinase inhibitor (Denki) PL265 in a murine model of neuropathic pain

“…Altogether, these results suggest that during the period of neuropathy development after PSNL PL265 could sufficiently protect enkephalins to maintain their concentrations at a level capable to stimulate the enkephalinergic system triggering subsequent long adaptive changes (Podvin et al, 2016). This stimulation would be strong enough to significantly alleviate symptoms of neuropathic pain in mice, even after interruption of PL265 administration.…”

Dynorphinergic system alterations in the corticostriatal circuitry of neuropathic mice support its role in the negative affective component of pain

“…Dynorphinergic system involvement in neuropathic pain has mainly been investigated at spinal level, 10,18,46 lates the pain control descending system. 29 Thus, our results indicate that after peripheral nerve injury Pdyn mRNA alterations, so far mainly reported at spinal level, 11,47,48 also occur in the cortical regions.…”

“…However, at post-SNL day 10 only, the Pdyn KO animals showed a return to nociceptive baseline values, suggesting that dynorphin could play a pronociceptive role through the maintenance of central sensitization. 18 In fact, when injected at relatively low doses, dynorphin exhibits antinociceptive properties mediated by κ-opioid receptor activation. 16,17 These different roles exerted by dynorphin (ie, pronociceptive and antinociceptive) can be mediated through opioid and non-opioid spinal mechanisms.…”

“…16,17 These different roles exerted by dynorphin (ie, pronociceptive and antinociceptive) can be mediated through opioid and non-opioid spinal mechanisms. 18 In fact, when injected at relatively low doses, dynorphin exhibits antinociceptive properties mediated by κ-opioid receptor activation. Conversely, the intrathecal administration of a high dose seems to activate N-methyl-D-aspartate (NMDA) receptors, producing non-opioid receptor-mediated neurotoxicity and hyperalgesia.…”

(206) Modulation of multiple modalities of somatosensory information by peripheral kappa opioid receptors

“…Although some studies have shown a pronociceptive effect of dynorphin signaling evidence suggests that this is through a non-opioid receptor mediated mechanism (for review see, (Podvin, Yaksh, & Hook, 2016)). The contribution of KORs on specific neuron types or in different regions of the pain pathway and how each might contribute to mediating distinct modalities of pain is less clear.…”