Effects of μ-Opioid Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Male Rats: Role of μ-Agonist Efficacy and Noxious Stimulus Intensity

Abstract

Pain is associated with stimulation of some behaviors and depression of others, and m-opioid receptor agonists are among the most widely used analgesics. This study used parallel assays of pain-stimulated and pain-depressed behavior in male SpragueDawley rats to compare antinociception profiles for six m-agonists that varied in efficacy at m-opioid receptors (from highest to lowest: methadone, fentanyl, morphine, hydrocodone, buprenorphine, and nalbuphine). Intraperitoneal injection of diluted lactic acid served as an acute noxious stimulus to either stimulate stretching or depress operant responding maintained by electrical stimulation in an intracranial self-stimulation (ICSS). All m-agonists blocked both stimulation of stretching and depression of ICSS produced by 1.8% lactic acid. The high-efficacy agonists methadone and fentanyl were more potent at blocking acid-induced depression of ICSS than acid-stimulated stretching, whereas lowerefficacy agonists displayed similar potency across assays. All m-agonists except morphine also facilitated ICSS in the absence of the noxious stimulus at doses similar to those that blocked acid-induced depression of ICSS. The potency of the low-efficacy m-agonist nalbuphine, but not the high-efficacy m-agonist methadone, to block acid-induced depression of ICSS was significantly reduced by increasing the intensity of the noxious stimulus to 5.6% acid. These results demonstrate sensitivity of acid-induced depression of ICSS to a range of clinically effective m-opioid analgesics and reveal distinctions between opioids based on efficacy at the m-receptor. These results also support the use of parallel assays of pain-stimulated and -depressed behaviors to evaluate analgesic efficacy of candidate drugs.

Expression and treatment of pain-related behavioral depression

“…These results are in agreement with those of other studies showing that NSAIDs block other forms of pain-related behavioral depression (Table 2) and have clinical efficacy in treating some types of pain. Similar results have been reported for μ-opioid agonists, the second major class of clinically effective analgesic drugs, including morphine, methadone, hydrocodone and buprenorphine 30,41 . These drugs dose-dependently block acid-induced depression of ICSS response rate while having little or no effect on response rate in the absence of the noxious stimulus 30,41 .…”

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

“…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). …”

Pharmacological modulation of neuropathic pain-related depression of behavior: effects of morphine, ketoprofen, bupropion and ∆9-tetrahydrocannabinol on formalin-induced depression of intracranial self-stimulation in rats

“…), or Δ 9 -tetrahydrocannabinol (THC; 0.32–3.2, i.p.). Doses, routes of administration, and pretreatment times were based on previous ICSS studies with morphine, ketoprofen, bupropion and THC (Altarifi et al, 2015; Kwilasz and Negus, 2012; Leitl et al, 2014b; Rosenberg et al, 2013). Next, on Days 8–13, the effects of repeated daily dosing with a single drug dose were examined.…”