Dual Regulation ofδ-Opioid Receptor Function by Arachidonic Acid Metabolites in Rat Peripheral Sensory Neurons

Abstract

The regulation of opioid receptor system function in peripheral sensory neurons is not well understood. Opioid agonist efficacy to inhibit nociceptor function and to promote antinociception is generally weak under basal conditions and frequently no response occurs. However, in response to a cyclooxygenasedependent metabolite of arachidonic acid (AA) after exposure to inflammatory mediators, such as bradykinin (BK) or exogenous AA, peripheral opioid receptor systems become much more responsive to opioid agonists. In this study, we examined the time course for the induction and maintenance of functional competence of the d-opioid receptor (DOR) system in adult rat nociceptors in culture and in vivo. We found that the responsive state of DOR after pretreatment with BK or exogenous AA is transient (30-60 minutes) and persists for 15-30 minutes after a 15-minute exposure of nociceptors to BK or AA. Interestingly, whereas functional competence of the DOR system could be reinduced with a second application of BK 60 minutes after the first, responsiveness of the DOR system could not be reinduced after an initial exposure to AA. This nonresponsive state of DOR after exogenous AA was mediated by a lipoxygenase (LOX)-dependent metabolite of AA. Intraplantar carrageenan also produced transient DOR functional competence and responsiveness was also reinduced by inhibition of LOX. Thus, the DOR system expressed by peripheral sensory neurons is under dual regulation by cyclooxygenase-and LOX-dependent metabolites of AA.

Long-Term Reduction of Kappa Opioid Receptor Function by the Biased Ligand, Norbinaltorphimine, Requires c-Jun N-Terminal Kinase Activity and New Protein Synthesis in Peripheral Sensory Neurons

“…Kappa opioid receptors expressed by peripheral painsensing neurons can produce robust antinociception; however, several cellular regulatory mechanisms, which may be unique to nociceptors, limit antinociceptive effectiveness of peripherally-restricted KOR agonists (Patwardhan et al, 2005;Berg et al, 2007Berg et al, , 2011Rowan et al, 2009;Jamshidi et al, 2015;Sullivan et al, 2015). If peripheral KOR is to be a viable therapeutic target for peripherally-restricted analgesics, it is important to understand these regulatory mechanisms.…”

“…After baseline PWL was determined, animals were pretreated with BK (25 mg) via intraplantar (i.pl.) injection to induce KOR functional competence (Rowan et al, 2009;Berg et al, 2011Berg et al, , 2012Jamshidi et al, 2015;Sullivan et al, 2015). To assess KOR-mediated antinociception, rats received coinjections (i.pl.)…”

“…Opioid receptor-mediated inhibition of adenylyl cyclase activity was determined by measuring the amount of cAMP accumulated (15 minutes) in the presence of the phosphodiesterase inhibitor, rolipram, and PGE 2 (1 mM) with or without the indicated opioid receptor ligands, as described previously (Patwardhan et al, 2005(Patwardhan et al, , 2006Berg et al, 2007Berg et al, , 2011Jamshidi et al, 2015;Sullivan et al, 2015). For all experiments, cells were pretreated with BK (10 mM, 15 minutes, 37°C) to induce KOR functional competence (Berg et al, 2007(Berg et al, , 2012Jamshidi et al, 2015;Sullivan et al, 2015). To assess long-term effects of norBNI on KOR agonist-mediated inhibition of PGE 2 -stimulated cAMP accumulation, cells were treated with norBNI (3 nM) for 1 hour, washed three times with 500 ml/well serum-free media (a total wash period of 30 minutes), and then incubated further for 24 hours (37°C, 5% CO 2 ) before testing KOR agonist efficacy.…”

“…Primary cultures derived from rat trigeminal ganglion were prepared, as described previously (Patwardhan et al, 2005(Patwardhan et al, , 2006Berg et al, 2007Berg et al, , 2011Jamshidi et al, 2015;Sullivan et al, 2015), and maintained in culture for 5 days. For all experiments, cells were refed with serum-free Dulbecco's modified Eagle's medium without nerve growth factor on day 5 and used for experiments on the sixth day of culture (i.e., after a 24-hour serum-and nerve growth factor-free period).…”

“…Similarly, opioid agonists do not produce inhibitory signaling in cultures of nociceptors unless the cells are first pretreated with an inflammatory mediator, such as bradykinin or arachidonic acid (Patwardhan et al, 2005;Berg et al, 2007Berg et al, , 2011Sullivan et al, 2015).…”