Papers of the Week

In addition to analgesia, opioids produce hyperalgesia (opioid-induced hyperalgesia [OIH]) and neuroplasticity characterized by prolongation of inflammatory mediator-induced hyperalgesia (hyperalgesic priming). We evaluated the hypothesis that hyperalgesia and priming induced by opioids, are mediated by similar nociceptor mechanisms. In male rats, we first evaluated the role of nociceptor toll-like receptor 4 (TLR4), in OIH and priming induced by systemic low dose morphine (LDM, 0.03 mg/kg). Intrathecal oligodeoxynucleotide antisense to TLR4 mRNA (TLR4 AS-ODN) prevented OIH and prolongation of PGE hyperalgesia (priming) induced by LDM. In contrast, high dose morphine (HDM, 3 mg/kg) increased nociceptive threshold (analgesia) and induced priming, neither of which were attenuated by TLR4 AS-ODN. Protein kinase C epsilon (PKCε) AS-ODN also prevented LDM-induced hyperalgesia and priming, while analgesia and priming induced by HDM were unaffected. Treatment with isolectin B4 (IB4)-saporin or SSP-saporin (which deplete IB4-positive [IB4] and peptidergic nociceptors, respectively), or their combination, prevented systemic LDM-induced hyperalgesia, but not priming. HDM-induced priming, but not analgesia, was markedly attenuated in both saporin-treated groups. In conclusion, while OIH and priming induced by LDM share receptor and second messenger mechanisms in common, action at TLR4 and signaling via PKCε, HDM-induced analgesia and priming are neither TLR4 nor PKCε dependent. OIH produced by LDM is mediated by both IB4 and peptidergic nociceptors, while priming is not dependent on the same population. In contrast, priming induced by HDM is mediated by both IB4 and peptidergic nociceptors. Implications for the use of low dose opioids combined with non-opioid analgesics and in treatment of opioid use disorder are discussed.Opioid-induced hyperalgesia (OIH) and priming are common side effects of opioid agonists, e.g., morphine, which acts at mu-opioid receptors (MORs). We demonstrate that OIH and priming induced by systemic low dose morphine (LDM) share action at TLR4 and signaling via PKCε, in common, while systemic high dose morphine (HDM)-induced analgesia and priming are neither TLR4 nor PKCε dependent. OIH produced by systemic LDM is mediated by IB4 and peptidergic nociceptors, while priming is dependent on a different class of nociceptors. Priming induced by systemic HDM is, however, mediated by both IB4 and peptidergic nociceptors. Our findings may provide useful information for use of low dose opioids combined with non-opioid analgesics to treat pain and opioid use disorders.