Neuroanatomical Mapping Studies of Opioid-Induced Analgesia

Shortly after the discovery of the opioid receptor in 1973, it became apparent that multiple opioid receptor subtypes (mu, delta, kappa and ORL-1) existed based on pharmacological, biochemical, anatomical and ultimately molecular evidence. Highly-specific and selective opioid receptor subtype agonists for the mu (e.g. DAMGO), delta-1 (e.g., DPDPE), delta-2 (e.g., deltorphin), kappa (e.g., U50488H) and ORL-1 (e.g., orphanin FQ-nociceptin) and antagonists for the mu (e.g., beta-funaltrexamine, CTOP), mu-1 (e.g., naloxonazine), delta (e.g., naltrindole) and kappa (e.g., nor-binaltorphamine) were developed and used by our laboratory and others to characterize which opioid receptor subtypes were involved in which sites in the brain to elicit opioid-induced analgesia. Based on the classic work of Basbaum and Fields, a number of highly-relevent supraspinal brain sites, including the periaqueductal gray (PAG), the rostroventromedial medulla (RVM), the locus coeruleus (LC) and the amygdala were evaluated for the ability of opioid receptor subtype agonists to elicit analgesia from a given site and the ability of different opioid receptor subtype antagonists to block the analgesia when delivered to the same site. Our laboratory began to explore regional interactions between these relevant sites in two ways: a) administering an antagonist in one site (e.g., RVM) to detect any changes in analgesia elicited by an agonist in another site (e.g., PAG); and b) administered a fixed dose of an agonist in one site eliciting a minimal analgesic effect (e.g., PAG) and then administering a range of sub-threshold doses of the same agonist in another site to detect additive or synergistic effects. The opioid, serotonergic, glutaminergic and cholinergic receptor systems in the RVM have been analyzed for morphine analgesia elicited from the PAG, and the opioid receptor system in the PAG have been analyzed for morphine and OFQ/N-induced analgesia elicited from the amygdala. Analgesic synergy has been observed for the PAG and RVM, the RVM and LC, the LC and PAG, and the PAG and amygdala.

Related Publications of the Bodnar Laboratory:

Shane, R, J Acosta, GC Rossi and RJ Bodnar. Reciprocal interactions between the amygdala and ventrolateral periaqueductal gray in mediating OFQ/N(1-17)-induced analgesia in the rat. Brain Res. 980: 57-70, 2003.

Shane, R, J Wolkin and RJ Bodnar. Reduction in OFQ/N(1-17)-induced analgesia elicited from the amygdala by pretreatment with mu, kappa and delta opioid antagonists in rats. Analgesia 6: 499-505, 2002.

Rossi, GC, R Shane, M Pellegrino, CA Abbadie, RJ Bodnar, JP Mathis, GW Pasternak and RG Allen. Characterization of rat preproOrphanin FQ/nociceptin (154-1817): nociceptive processing in supraspinal sites. J. Pharmacol. Exp. Ther. 300: 257-264, 2002.

Shane, R, DA Lazar, GC Rossi, GW Pasternak and RJ Bodnar. Analgesia elicited by OFQ/ nociceptin and its fragments from the amygdala in rats. Brain Res. 907: 109-116, 2001. Bodnar, RJ. Supraspinal circuitry mediating opioid antinociception: antagonist and synergy studies in multiple sites. J. Biomed. Sci. 7: 181-194, 2000.

Spinella,M, V Znamensky, M Moroz, A Ragnauth and RJ Bodnar. Actions of NMDA and cholinergic receptor antagonists in the rostral ventromedial medulla upon B-endorphin analgesia elicited from the ventrolateral periaqueductal gray. Brain Res. 829: 151-159, 1999.

Krzanowska, E, GC Rossi, GW Pasternak and RJ Bodnar. Potency ratios of morphine and morphine-6ß-glucuronide analgesia elicited from the periaqueductal gray, locus coeruleus or rostral ventromedial medulla of rats. Brain Res. 799:329-333, 1998.

Pavlovic, ZW and RJ Bodnar. U50488H-induced analgesia in the amygdala: test-specific effects and blockade by opioid antagonists in the periaqueductal gray. Analgesia 3: 223-230, 1998.
Pavlovic, ZW and RJ Bodnar. Opioid supraspinal analgesic synergy between the amygdala and periaqueductal gray in rats. Brain Res. 779: 158-169, 1998.

Spinella, M, LA Schaefer and RJ Bodnar. Ventral medullary mediation of mesencephalic morphine analgesia by muscarinic and nicotinic cholinergic receptor antagonists in rats. Analgesia 3: 119-130, 1997. Pavlovic, ZW, ML Cooper and RJ Bodnar. Opioid antagonists in the periaqueductal gray inhibit morphine and beta-endorphin analgesia elicited from the amygdala of rats. Brain Res. 741: 13-26, 1996. Spinella, M, ML Cooper and RJ Bodnar. Excitatory amino acid antagonists in the rostral ventromedial medulla inhibit mesencephalic morphine analgesia in rats. Pain 64: 545-552, 1996.

Nalwalk, JW, JE Koch, KE Barke, RJ Bodnar and LB Hough. Modulation of morphine antinociception by the brain-penetrating H2 antagonist zolantidine: detailed characterization in four nociceptive test systems. Pharmacol. Biochem. Behav. 50: 421-429, 1995.

Rossi, GC, GW Pasternak and RJ Bodnar. Mu and delta opioid synergy between the periaqueductal gray and the rostro-ventral medulla. Brain Res. 665: 85-93, 1994.

Rossi, GC, GW Pasternak and RJ Bodnar. Synergistic brainstem interactions for morphine analgesia. Brain Res. 624: 171-180, 1993.

Kiefel, JM, GC Rossi and RJ Bodnar. Medullary mu and delta opioid receptors modulate mesencephalic morphine analgesia in rats. Brain Res. 624: 151-161, 1993.

Kiefel, JM, ML Cooper and RJ Bodnar. Serotonin receptor subtype antagonists in the medial ventral medulla inhibit mesencephalic opiate analgesia. Brain Res. 597: 331-338, 1992.

Kiefel, JM, ML Cooper and RJ Bodnar. Inhibition of mesencephalic morphine analgesia by methysergide in the medial ventral medulla of rats. Physiol. Behav. 51: 201-205, 1992.

Kest, B, M Orlowski and RJ Bodnar. Endopeptidase 24.15 inhibition and opioid antinociception. Psychopharmacol. 106: 408-416, 1992.

Bodnar, RJ, D Paul and GW Pasternak. Synergistic analgesic interactions between the periaqueductal gray and the locus coeruleus: Studies with the partial mu1 agonist ethylketocyclazocine. Brain Res. 558: 224-230, 1991.

Kest, B, M Orlowski, C Molineaux and RJ Bodnar. Antinociceptive properties of inhibitors of endopeptidase 24.15. Int. J. Neurosci. 56: 141-149, 1991.

Bodnar, RJ, D Paul, M Rosenblum, L Liu and GW Pasternak. Blockade of morphine analgesia by both pertussis and cholera toxins in the periaqueductal gray and locus coeruleus. Brain Res. 529: 324-328, 1990.
Bodnar, RJ, D Paul and GW Pasternak. Proglumide selectively potentiates mu1 mechanisms of opioid analgesia. Neuropharmacol. 29: 507-510, 1990.

Paul, D, RJ Bodnar, MA Gistrak and GW Pasternak. Different mu receptor subtypes mediate spinal and supraspinal analgesia in mice. Eur. J. Pharmacol. 168: 307-314, 1989.

Bodnar, RJ, JA Clark, ML Cooper and GW Pasternak. Loss of striatal mu1 opiate receptors by substantia nigra lesions in the rat. Life Sci. 43: 1697-1700, 1988.

Williams, CL, RJ Bodnar, JA Clark, EF Hahn, TF Burks and GW Pasternak. Irreversible opiate agonists and antagonists: IV. Analgesic actions of 14-hydroxydihydromorphinone hydrazones. J. Pharmacol. Exp. Ther. 245: 8-12, 1988.

Bodnar, RJ, CL Williams, SJ Lee and GW Pasternak. Role of mu1 opiate receptors in supraspinal opiate analgesia: a microinjection study. Brain Res. 447: 25-34, 1988.

Pasternak, GW, RJ Bodnar, JA Clark and CE Inturrisi. Morphine-6-glucuronide, a potent mu agonist. Life Sci. 41: 2845-2849, 1987.

Romero, M-T and RJ Bodnar. Maintainance of beta-endorphin analgesia across age cohorts. Neurobiol. Aging 8: 167-170, 1987.

Kramer, E and RJ Bodnar. Age-related decrements in morphine analgesia: a parametric analysis. Neurobiol. Aging 7: 185-191, 1986.

Simone, DA, RJ Bodnar, T Portzline and GW Pasternak. Antagonism of morphine analgesia by intracerebroventricular naloxonazine. Pharmacol. Biochem. Behav. 24: 1721-1727, 1986.

Sperber, ES, M-T Romero and RJ Bodnar. Selective potentiations in opioid analgesia following scopolamine pretreatment. Psychopharmacol. 89: 175-176, 1986.

Bodnar, RJ, T Portzline and G Nilaver. Differential alterations in opioid analgesia following neonatal monosodium glutamate treatment. Brain Res. Bull. 15: 299-305, 1985.

Bodnar, RJ, G Nilaver, MM Wallace, D Badillo-Martinez and EA Zimmerman. Pain threshold changes in rats following central injection of beta-endorphin, met-enkephalin, vasopressin or oxytocin antisera. Int. J. Neurosci. 24: 149-160, 1984.

Bodnar, RJ, JH Kordower, A Reches, MM Wallace and S Fahn. Reductions in pain thresholds and morphine analgesia following intracerebroventricular parachlorophenylalanine. Pharmacol. Biochem. Behav. 21: 79-84, 1984.