Publications

We previously developed a model of opioid-induced neuroplasticity in the peripheral terminal of the nociceptor that could contribute to opioid-induced hyperalgesia, type II hyperalgesic priming. Repeated administration of mu-opioid receptor (MOR) agonists, such as DAMGO, at the peripheral terminal of the nociceptor, induces long-lasting plasticity expressed, prototypically as opioid-induced hyperalgesia and prolongation of prostaglandin E2-induced hyperalgesia. In this study, we evaluated the mechanisms involved in the maintenance of type II priming. Opioid receptor antagonist, naloxone, induced hyperalgesia in DAMGO-primed paws. When repeatedly injected, naloxone-induced hyperalgesia, and hyperalgesic priming, supporting the suggestion that maintenance of priming involves changes in MOR signaling. However, the knockdown of MOR with oligodeoxynucleotide antisense did not reverse priming. Mitogen-activated protein kinase and focal adhesion kinase, which are involved in the Src signaling pathway, previously implicated in type II priming, also inhibited the expression, but not maintenance of priming. However, when Src and mitogen-activated protein kinase inhibitors were coadministered, type II priming was reversed, in male rats. A second model of priming, latent sensitization, induced by complete Freund's adjuvant was also reversed, in males. In females, the inhibitor combination was only able to inhibit the expression and maintenance of DAMGO-induced priming when knockdown of G-protein-coupled estrogen receptor 30 (GPR30) in the nociceptor was performed. These findings demonstrate that the maintenance of DAMGO-induced type II priming, and latent sensitization is mediated by an interaction between, Src and MAP kinases, which in females is GPR30 dependent.

Neonatal pain has been suggested to contribute to the development and/or persistence of adult pain. Observations from animal models have shown that neonatal inflammation produces long-term changes in sensory neuron function, which can affect the susceptibility of adults to develop persistent pain. We used a preclinical model of transition to chronic pain, hyperalgesic priming, in which a previous inflammatory stimulus triggers a long-lasting increase in responsiveness to pro-algesic mediators, prototypically prostaglandin E (PGE), to investigate if post-natal age influences susceptibility of adult rats to develop chronic pain. Priming was induced by tumor necrosis factor alpha (TNFα), in male and female rats, 1, 2, 3, 4, 5 or 7weeks after birth. When adults (8weeks after birth), to evaluate for the presence of priming, PGE was injected at the same site as TNFα. In males that had received TNFα at post-natal weeks 1, 2 or 3, priming was attenuated compared to the 4-, 5- and 7-week-old treated groups, in which robust priming developed. In contrast, in females treated with TNFα at post-natal week 1, 2, 3, or 4, but not at 5 or 7, priming was present. This age and sex difference in the susceptibility to priming was estrogen-dependent, since injection of TNFα in 3-week-old males and 5-week-old females, in the presence of the estrogen receptor antagonist ICI 182,780, did produce priming. These results suggest that estrogen levels, which vary differently in males and females over the post-natal period, until they stabilize after puberty, impact pain as an adult.

INTRODUCTION

Group visits for advance care planning (ACP) may help patients document preferences for decision makers and future care. We assessed the impact of a primary care-based ACP group visit (ACP-GV) intervention on older adults' ACP documentation and why patients participated.

METHODS

Older adults (>65 years) in primary care participated in a 2-session ACP-GV intervention that promotes group dynamics, peer-based learning, and goal setting. Charts were reviewed at baseline, 3 months, and 12 months for documentation of decision makers and ACP forms. We described patients' reasons for participating through analysis of transcripts.

RESULTS

118 patients (mean age 76 years; 62% female and 82% white) participated in 16 ACP-GV cohorts. From baseline to 3-month follow-up, documentation of decision maker preferences increased from 39% to 81%, and was 89% at 12-month follow-up. Patients with completed ACP forms increased from 20% to 57% at 3 months, and was 67% at 12 months. Reasons for participating included recognizing the importance of ACP, curiosity, participation recommended by primary care provider, desire to talk with family/friends, and desire to complete advance directives.

CONCLUSIONS

This ACP-GV intervention increased ACP documentation among patients with diverse reasons for participating. This is a patient-centered approach to ACP in primary care.