Publications

Hyperalgesic priming, a model of pain chronification in the rat, is mediated by ryanodine receptor-dependent calcium release. Although ryanodine induces priming in both sexes, females are 5 orders of magnitude more sensitive, by an estrogen receptor α (EsRα)-dependent mechanism. An inositol 1,4,5-triphosphate (IP) receptor inhibitor prevented the induction of priming by ryanodine. For IP induced priming, females were also more sensitive. IP-induced priming was prevented by pretreatment with inhibitors of the sarcoendoplasmic reticulum calcium ATPase and ryanodine receptor. Antisense to EsRα prevented the induction of priming by low-dose IP in females. The induction of priming by an EsRα agonist was ryanodine receptor-dependent and prevented by the IP antagonist. Thus, an EsRα-dependent bidirectional interaction between endoplasmic reticulum IP and ryanodine receptor-mediated calcium signaling is present in the induction of hyperalgesic priming, in females. In cultured male DRG neurons, IP (100 μm) potentiated depolarization-induced transients produced by extracellular application of high-potassium solution (20 mm, K20), in nociceptors incubated with β-estradiol. This potentiation of depolarization-induced calcium transients was blocked by the IP antagonist, and not observed in the absence of IP IP potentiation was also blocked by ryanodine receptor antagonist. The application of ryanodine (2 nm), instead of IP, also potentiated K20-induced calcium transients in the presence of β-estradiol, in an IP receptor-dependent manner. Our results point to an EsRα-dependent, reciprocal interaction between IP and ryanodine receptors that contributes to sex differences in hyperalgesic priming. The present study demonstrates a mechanism that plays a role in the marked sexual dimorphism observed in a model of the transition to chronic pain, hyperalgesic priming. This mechanism involves a reciprocal interaction between the endoplasmic reticulum receptors, IP and ryanodine, in the induction of priming, regulated by estrogen receptor α in the nociceptor of female rats. The presence of this signaling pathway modulating the susceptibility of nociceptors to develop plasticity may contribute to our understanding of sex differences observed clinically in chronic pain syndromes.

BACKGROUND

As resources are deployed to address the opioid overdose epidemic in the USA, it is essential that we understand the correlates of more frequent opioid injections-which has been associated not only with HIV and HCV transmission, but also with overdose risk-to inform the development and targeting of effective intervention strategies like overdose prevention and naloxone distribution programs. However, no studies have explored how characteristics of opioid use partnerships may be associated within injection frequency with opioid partnerships.

METHODS

Using baseline data from a trial of a behavioural intervention to reduce overdose among opioid users in San Francisco, CA, we calculated assortativity among opioid use partnerships by race, gender, participant-reported HIV- and HCV-status, and opioids used using Newman's assortativity coefficient (NC). Multivariable generalized estimating equations linear regression was used to examine associations between individual- and partnership-level characteristics and injection frequency within opioid use partnerships.

RESULTS

Opioid use partnerships (n=134) reported by study participants (n=55) were assortative by race (NC=0.42, 95%CI=0.33-0.50) and participant-reported HCV-status (NC=0.42, 95%CI=0.31-0.52). In multivariable analyses, there were more monthly injections among sexual/romantic partnerships (β=114.4, 95%CI=60.2-168.7, p<0.001), racially concordant partnerships reported by white study participants (β=71.4, 95%CI=0.3-142.5, p=0.049), racially discordant partnerships reported by African American study participants (β=105.7, 95%CI=1.0-210.5, p=0.048), and partnerships in which either member had witnessed the other experience an overdose (β=81.8, 95%CI=38.9-124.6, p<0.001).

CONCLUSION

Social segregation by race and HCV-status should potentially be considered in efforts to reach networks of opioid users. Due to higher injection frequency and greater likelihood of witnessing their partners experience an overdose, individuals in sexual/romantic opioid use partnerships, white individuals in racially homogenous partnerships, and African American individuals in heterogeneous partnerships may warrant focused attention as part of peer- and network-based overdose prevention efforts, as well as broader HIV/HCV prevention strategies. Developing and targeting overdose prevention education programs that provide information on risk factors and ways to identify overdose, as well as effective responses, including naloxone use and rescue breathing, for more frequently injecting networks may help reduce opioid morbidity and mortality in these most at risk groups.