Effects of pain- and analgesia-related manipulations on intracranial self-stimulation in rats: Further studies on pain-depressed behavior

Abstract

Pain stimulates some behaviors (e.g. withdrawal responses) but depresses many other behaviors (e.g. feeding). Pain-stimulated behaviors are widely used in preclinical research on pain and analgesia, but human and veterinary medicine often rely on measures of functional impairment and paindepressed behavior to diagnose pain or assess analgesic efficacy. In view of the clinical utility of measures of pain-depressed behaviors, our laboratory has focused on methods development for preclinical assays of pain-depressed behavior in rodents. The present study compared the effects of a chemical noxious stimulus (IP lactic acid injections) and an opioid analgesic (morphine) administered alone or in combination on the stretching response (a pain-stimulated behavior) and intracranial self-stimulation (ICSS; a behavior that may be depressed by pain) in rats. For the ICSS procedure, rats implanted with electrodes in the lateral hypothalamus responded for electrical stimulation across a range of current frequencies to permit rapid determination of frequency-rate curves and evaluation of curve shifts following treatment. Lactic acid alone produced a concentrationdependent stimulation of stretching and depression of ICSS, expressed as rightward shifts in ICSS frequency-rate curves. Morphine had little effect alone, but it produced a dose-dependent blockade of both acid-stimulated stretching and acid-depressed ICSS. Both lactic acid and morphine were equipotent in the stretching and ICSS procedures. These results suggest that ICSS may be useful as a behavioral baseline for studies of pain-depressed behavior.

Differential tolerance to morphine antinociception in assays of pain-stimulated vs. pain-depressed behavior in rats

“…The nociceptive effects of intraperitoneal lactic acid in this study agree with previous findings from our laboratory (Pereira Do Carmo et al, 2009; Negus et al, 2010). For example, we reported previously that intraperitoneal lactic acid is equipotent to stimulate a stretching response and to depress ICSS in rats (Pereira Do Carmo et al, 2009).…”

“…We have shown previously that morphine produces dose-dependent and equipotent antinociception in both assays (Pereira Do Carmo et al, 2009; Altarifi et al, in press ). The goal of this study was to assess the degree to which morphine tolerance might also be similar across these two assays.…”

“…For example, we reported previously that intraperitoneal lactic acid is equipotent to stimulate a stretching response and to depress ICSS in rats (Pereira Do Carmo et al, 2009). Similarly, the antinociceptive effects of morphine observed here also agree with previous studies using morphine and other mu opioid analgesics (Pereira Do Carmo et al, 2009; Negus and Altarifi, 2013; Negus, 2013; Altarifi et al, in press ).…”

“…For example, we reported previously that intraperitoneal lactic acid is equipotent to stimulate a stretching response and to depress ICSS in rats (Pereira Do Carmo et al, 2009). Similarly, the antinociceptive effects of morphine observed here also agree with previous studies using morphine and other mu opioid analgesics (Pereira Do Carmo et al, 2009; Negus and Altarifi, 2013; Negus, 2013; Altarifi et al, in press ). In particular, we have shown previously that morphine is equipotent to block both acid-stimulated stretching and acid-induced depression of ICSS in rats, with complete antinociception in both procedures at a morphine dose of 1.0 mg/kg (Pereira Do Carmo et al, 2009; Altarifi et al, 2014).…”

Using a rate-frequency curve method to assess the rewarding properties of morphine in the intracranial self-stimulation paradigm in rats

“…While there are a few studies to date that report effects of morphine using the ICSS paradigm, such as the series conducted by Kornetsky and colleagues (Kornetsky et al, 1979;Hubner and Kornetsky, 1992), acute administration of morphine has failed to produce robust and reliable leftward shifts in brain stimulation reward (Hand and Franklin, 1986;Carlezon and Wise, 1993;Easterling et al, 2000;Do Carmo et al, 2009;S.S. Negus and J.R. Stellar, personal communication).…”