Morphine Antinociceptive Potency on Chemical, Mechanical, and Thermal Nociceptive Tests in the Rat

Morgan, Michael M.; Fossum, Erin N.; Stalding, Brandon M.; King, Melissa M.

doi:10.1016/j.jpain.2005.12.009

Cited by 68 publications

(48 citation statements)

References 15 publications

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“…APAP alone had no effect on tail flick latencies (no significant difference from baseline latencies) during the 30-120-minute time course or at 3 hours or 6 hours (data not shown). Morphine alone (30-120 minutes) exhibited increases in tail flick latencies that were directly comparable to previously published work (data not shown; Shen and Crain, 1997;Morgan et al, 2006). In accordance with previous findings for morphine (Shen and Crain, 1997), analgesia in all animals treated with morphine or morphine with APAP peaked 60 minutes postmorphine treatment (Fig.…”

Section: Apap Increases P-gp Protein Expression In Isolatedsupporting

confidence: 91%

Acetaminophen Modulates P-Glycoprotein Functional Expression at the Blood-Brain Barrier by a Constitutive Androstane Receptor–Dependent Mechanism

et al. 2013

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Effective pharmacologic treatment of pain with opioids requires that these drugs attain efficacious concentrations in the central nervous system (CNS). A primary determinant of CNS drug permeation is P-glycoprotein (P-gp), an endogenous blood-brain barrier (BBB) efflux transporter that is involved in brain-to-blood transport of opioid analgesics (i.e., morphine). Recently, the nuclear receptor constitutive androstane receptor (CAR) has been identified as a regulator of P-gp functional expression at the BBB. This is critical to pharmacotherapy of pain/inflammation, as patients are often administered acetaminophen (APAP), a CAR-activating ligand, in conjunction with an opioid. Our objective was to investigate, in vivo, the role of CAR in regulation of P-gp at the BBB. Following APAP treatment, P-gp protein expression was increased up to 1.4-1.6-fold in a concentration-dependent manner.Additionally, APAP increased P-gp transport of BODIPY-verapamil in freshly isolated rat brain capillaries. This APAP-induced increase in P-gp expression and activity was attenuated in the presence of CAR pathway inhibitor okadaic acid or transcriptional inhibitor actinomycin D, suggesting P-gp regulation is CAR-dependent. Furthermore, morphine brain accumulation was enhanced by P-gp inhibitors in APAP-treated animals, suggesting P-gp-mediated transport. A warm-water (50°C) tail-flick assay revealed a significant decrease in morphine analgesia in animals treated with morphine 3 or 6 hours after APAP treatment, as compared with animals treated concurrently. Taken together, our data imply that inclusion of APAP in a pain treatment regimen activates CAR at the BBB and increases P-gp functional expression, a clinically significant drugdrug interaction that modulates opioid analgesic efficacy.

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Section: Apap Increases P-gp Protein Expression In Isolatedsupporting

confidence: 91%

Acetaminophen Modulates P-Glycoprotein Functional Expression at the Blood-Brain Barrier by a Constitutive Androstane Receptor–Dependent Mechanism

et al. 2013

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“…This observed analgesia was expected because the half-life of s.c. administered morphine is reported to be 5 h in the rat (Mullis et al, 1979). Thus, a little less than 10 mg/kg remained in the circulation 12 h after a 40 mg/kg treatment, a concentration that is reported to exceed morphine's antinociceptive ED 50 to a variety of noxious stimuli (Morgan et al, 2006). These findings may reflect the bidirectional first and second order effects of opioid signal transduction (e.g., Colpaert, 1996).…”

Section: Discussionmentioning

confidence: 99%

Morphine Deprivation Increases Self-Administration of the Fast- and Short-Acting μ-Opioid Receptor Agonist Remifentanil in the Rat

Cooper

Truong

Shi

et al. 2008

J Pharmacol Exp Ther

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Opiate dependence and withdrawal have long been hypothesized to enhance the reinforcing effects of opiates; however, opiate agonist self-administration in these states has yet to be systematically assessed. To address this issue, the reinforcing property of the short-acting -opioid agonist, remifentanil, was assessed in morphine-dependent (MD), morphine-dependent and -withdrawn (MW), and nondependent, control (C) rats. Dependence was established by twice daily administration of increasing doses of morphine for 4 days (10, 20, 30, and 40 mg/kg s.c.) and then maintained with a daily injection of the large dose. Morphine deprivation-induced withdrawal (defined by weight loss and hyperalgesia) was apparent 24, but not 12, h after morphine treatment. Remifentanil self-administration (0.4, 0.8, 1.6, 3.2, or 6.4 g/kg/infusion) was assessed over 20 successive, daily, 1-h sessions, either 12 or 24 h after the maintenance dose of morphine. Compared with the control group, the MD group demonstrated suppressed remifentanil self-administration, whereas the MW group exhibited enhanced responding for every dose of remifentanil. The increased responding observed in the MW group compared with the control and MD groups resulted in an upward shift in the remifentanil dose-response curve, an effect that was expressed only after repeated exposure to the contingency, demonstrating that morphine withdrawal ultimately enhances the reinforcing effects of remifentanil.

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“…The formalin test elicits persistent nocifensive behavior that has been shown sensitive to opiates (Morgan et al, 2006). We compared the behavioral responses to subcutaneous injection of 25 l (5%) of formalin into one hindpaw in Derm-sap and PBS control These experiments used Long-Evans female rats (n ϭ 7) with indwelling intrathecal catheters.…”

Section: Formalin Testmentioning

confidence: 99%

Spinal μ-Opioid Receptor-Expressing Dorsal Horn Neurons: Role in Nociception and Morphine Antinociception

Kline¹,

Wiley²

2008

J. Neurosci.

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The role of spinal cord -opioid receptor (MOR)-expressing dorsal horn neurons in nociception and morphine analgesia is incompletely understood. Using intrathecal dermorphin-saporin (Derm-sap) to selectively destroy MOR-expressing dorsal horn neurons, we sought to determine the role of these neurons in (1) normal baseline reflex nocifensive responses to noxious thermal stimulation (hotplate, tail flick) and to persistent noxious chemical stimulation (formalin) and (2) the antinociceptive activity of intrathecal and systemic morphine in the same tests. Lumbar intrathecal Derm-sap (500 ng) produced (1) partial loss of lamina II MOR-expressing dorsal horn neurons, (2) no effect on MOR-expressing dorsal root ganglion neurons, and (3) no change in baseline tail-flick and hotplate reflex nocifensive responses. Derm-sap treatment attenuated the antinociceptive action of both intrathecal and systemic morphine on hotplate responses. Derm-sap treatment had two effects in the formalin test: (1) increased baseline nocifensive responding and (2) reduced antinociceptive action of systemic morphine. We conclude that MOR-expressing dorsal horn neurons (1) are not essential for determining nocifensive reflex responsiveness to noxious thermal stimuli, (2) are necessary for full antinociceptive action of morphine (intrathecal or systemic) in these tests, and (3) play a significant role in the endogenous modulation of reflex nocifensive responses to persistent pain in the formalin test. Thus, one would predict that altering the activity of MOR-expressing dorsal horn neurons would be antinociceptive and of interest in the search for new approaches to management of chronic pain.

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Morphine Antinociceptive Potency on Chemical, Mechanical, and Thermal Nociceptive Tests in the Rat

Cited by 68 publications

References 15 publications

Acetaminophen Modulates P-Glycoprotein Functional Expression at the Blood-Brain Barrier by a Constitutive Androstane Receptor–Dependent Mechanism

Acetaminophen Modulates P-Glycoprotein Functional Expression at the Blood-Brain Barrier by a Constitutive Androstane Receptor–Dependent Mechanism

Morphine Deprivation Increases Self-Administration of the Fast- and Short-Acting μ-Opioid Receptor Agonist Remifentanil in the Rat

Spinal μ-Opioid Receptor-Expressing Dorsal Horn Neurons: Role in Nociception and Morphine Antinociception

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