This study investigated opioid signaling in DRG neurons to elucidate mechanisms underlying chronic morphine-induced side effects: tolerance and opioid-induced hyperalgesia (OIH). Our goal was to identify novel molecular targets to improve the safety and effectiveness of opioid therapy.

Mu opioid receptors are widely expressed in pain pathways, including dorsal root ganglia (DRG) neurons. Morphine acts by inhibiting adenylyl cyclase (AC), reducing calcium influx, neurotransmitter release, and activating GIRK channels, leading to neuronal inhibition. The ER chaperone sigma-1 receptor (Sig-1R) was demonstrated to play a role in neuropathic pain and is known to exist in the DRG.

Subcutaneous (sc) 10mg/kg 8 day morphine injection was used to induce tolerance and hyperalgesia in wild type (WT) and Sig-1R knock out (KO) mice. Response to treatment was assessed by Von-Frey filaments and tail-flick test. DRGs were harvested and used for molecular, biochemical and histopathological analysis.

Chronic morphine administration induced mechanical hyperalgesia in WT but not in Sig-1R KO mice, both genotypes developed tolerance. 

While the acute effects of opioid administration involve inhibitory effects on AC, chronic administration reveals super activation of AC. We measured cAMP level in dissociated DRG neurons from saline and morphine injected animals.  Increase in cAMP was seen after chronic morphine treatment in WT animals and the same was not observed in Sig-1R KO mice. 

Thus AC super activation/overshooting could be proposed as tentative underlying mechanism of OIH at DRG and Sig-1R plays a role in developing this phenomenon. Our immunohistochemistry study revealed increased perinuclear localization of Sig-1R in DRG following chronic morphine treatment. This suggests that Sig-1R may play a role in the development of OIH, potentially through modulation of epigenetic or transcriptional responses. Further studies are underway to elucidate the molecular mechanisms underlying this interaction.