κ-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats

Abstract

Although opioids are potent analgesics, a consequence of chronic opioid use is hyperalgesia during withdrawal, which may contribute to opioid misuse. Dynorphin, the endogenous ligand of κ-opioid receptors (KORs), is upregulated in opioid-dependent rats and in animal models of chronic pain. However, the role of KORs in opioid withdrawal-induced hyperalgesia remains to be determined. We hypothesized that KOR antagonism would reverse opioid withdrawal-induced hyperalgesia in opioid-dependent rats. Male and female Wistar rats received daily injections of heroin (2–6 mg/kg, SC) and were tested for mechanical sensitivity in the electronic von Frey test 4–6 h into withdrawal. Female rats required significantly more heroin than male rats to reach comparable levels of both heroin-induced analgesia and hyperalgesia (6 mg/kg vs. 2 mg/kg). Once hyperalgesia was established, we tested the effects of the KOR antagonists nor-binaltorphimine (norBNI; 30 mg/kg, SC) and 5′-guanidinonaltrindole (5′GNTI; 30 mg/kg, SC). When the animals continued to receive their daily heroin treatment (or saline treatment in the repeated saline group) five times per week throughout the experiment, both KOR antagonists reversed heroin withdrawal-induced hyperalgesia. The anti-hyperalgesia effect of norBNI was more prolonged in males than in females (14 days vs. 7 days), whereas 5′GNTI had more prolonged effects in females than in males (14 days vs. 4 days). The behavioral effects of 5′GNTI coincided with higher 5′GNTI levels in the brain than in plasma when measured at 24 h, whereas 5′GNTI did not reverse hyperalgesia at 30 min posttreatment when 5′GNTI levels were higher in plasma than in the brain. Finally, we tested the effects of 5′GNTI on naloxone-induced and spontaneous signs of opioid withdrawal and found no effect in either male or female rats. These findings indicate a functional role for KORs in heroin withdrawal-induced hyperalgesia that is observed in rats of both sexes.

Neuronal Correlates of Hyperalgesia and Somatic Signs of Heroin Withdrawal in Male and Female Mice

“…Although some studies identified sex differences in hyperalgesia during heroin withdrawal in rats ( Marchette et al, 2021 ), we did not find sex differences in the present study in mice. In addition to species differences and specific timepoints of behavior assessment, the lack of sex differences in the present study may have resulted from the use of relatively high doses of heroin in both male and female mice (40–50 mg/kg twice daily).…”

“…Both distinct and similar cellular and molecular mechanisms have been linked to hyperalgesia and somatic withdrawal ( Maldonado et al, 1996 ; Largent-Milnes et al, 2008 ; Tsai et al, 2009 ; Corder et al, 2013 ; Brust et al, 2015 ). For example, κ-opioid receptor antagonism reversed hyperalgesia during spontaneous heroin withdrawal in male and female rats but did not affect somatic withdrawal ( Marchette et al, 2021 ). However, antagonists of NMDA glutamate receptors, β2-adrenergic receptors, serotonin 5-hydroxytryptamine-3 (5-HT 3 ) receptors, and corticotropin-releasing factor 1 (CRF 1 ) receptors attenuated both somatic withdrawal ( Pinelli et al, 1997 ; Lu et al, 2000 ; Liang et al, 2007 ; Higgins et al, 2019 ) and hyperalgesia ( Higgins et al, 1992 ; Liang et al, 2006 , 2011 ; Harris et al, 2008 ; Park et al, 2015 ) in male rats and mice.…”

“…Although sex differences in opioid dependence have been reported in humans and rodents ( Zachry et al, 2019 ; Marchette et al, 2021 ; Pantazis et al, 2021 ), most studies were conducted in male subjects. Previous studies found that female opioid-dependent mice and rats exhibited similar levels of somatic signs of naloxone-precipitated heroin withdrawal compared with male opioid-dependent mice and rats ( Cicero et al, 2002 ; Towers et al, 2019 ).…”

Alleviation of Cocaine Withdrawal and Pertinent Interactions between Salvinorin-based Antagonists and Kappa Opioid Receptor

“…18 KOR antagonism was also recently shown to reverse heroin withdrawal-induced hyperalgesia in male and female rats. 19 These results suggested that antagonizing KOR may halt some depressive and anxiety-related symptoms that are associated with withdrawal, along with motivational withdrawal symptoms, to ultimately reduce drug use relapse.…”

Alleviation of Cocaine Withdrawal and Pertinent Interactions between Salvinorin-based Antagonists and Kappa Opioid Receptor

“…17 KOR antagonism was also recently shown to reverse heroin withdrawal-induced hyperalgesia in male and female rats. 18 These results suggested that antagonizing KOR may halt some depressive and anxiety-related symptoms that are associated with withdrawal, along with motivational withdrawal symptoms, to ultimately reduce drug use relapse.…”