Systemic physostigmine increases the antinociceptive effect of spinal morphine B. Beilin a , A.Y. Nemirovsky b, *, A. Zeidel a , E. Maibord a , V. Zelman b , R.L. Katz b a Department of Anesthesiology, Rabin Medical Center, Golda Campus, Petach-Tikva, Israel b Department of Anesthesiology, University of Southern California, 1200 North State Street, Room 14–901, Los Angeles, CA 90033, USA Received 15 March 1996; revised version received 25 November 1996; accepted 11 December 1996 Abstract In this study we evaluated the antinociceptive effect of concurrent intrathecal (i.t.) and subcutaneous (s.c.) administration of morphine and physostigmine, respectively. The experiments were performed on male Wistar rats. Intrathecal administration of morphine was performed through a catheter implanted in the subarachnoid space. The ‘tail-immersion’ test was used to measure animals’ responses to evoked nociceptive stimuli. Interaction of drugs was analyzed using a dose addition model. Both i.t. (1–5 mg) administration of morphine and s.c. (50–250 mg/kg) administration of physostigmine increased the latencies of nociceptive responses in a dose-dependent manner. Two micrograms of i.t. morphine and 100 mg/kg of s.c. physostigmine demonstrated 31.6 ± 10.6 and 34.2 ± 11.4 percentage of maximal possible effect (%MPE), respectively. Simultaneous administration of 1 mg of i.t. morphine and 50 mg/kg of s.c. physostigmine produced a %MPE equal to 84.8 ± 16.9. Thus, combined administration of 1 mg i.t. morphine and 50 mg/kg s.c. physostigmine resulted in a strong, highly significant antinociceptive effect. This effect was much higher than the effect expected if both drugs acted in an additive manner. Supra-additive interaction observed in this study might be a result of simultaneous activation of different neurotrans- mitter systems involved in nociceptive processing at the spinal as well as at the supraspinal level of the CNS.  1997 International Association for the Study of Pain. Published by Elsevier Science B.V. Keywords: Morphine; Physostigmine; Intrathecal and subcutaneous administration; Antinociception; Supra-additive interaction 1. Introduction One of the possibilities to increase the efficacy of analgesic treatment is to employ drug combinations which are able to trigger different endogenous antinoci- ceptive mechanisms. This can be accomplished in several ways. First, by combining drugs with different pharmaco- logical mechanisms. Thus, combinations of opioids with NSAIDs, local anesthetics, adrenergic and cholinergic drugs were demonstrated to result in an increased analge- sic effect (Akerman et al., 1988; Ossipov et al., 1990; Plummer et al., 1992; Malmberg and Yaksh, 1993; for review see Nemirovsky and Niv, 1997). A second way of increasing antinociceptive effect is to combine different routes of administration of drugs from the same pharmacological group (for example, spinal and supraspinal administration of opioids), thus activating antinociceptive systems located at different levels of the neuraxis. It was previously shown that concurrent admin- istration of opioids to the spinal cord and brain ventricles (Yeung and Rudy, 1980; Roerig and Fujimoto, 1989; Miaskowski and Levine, 1992; Miaskowski et al., 1993) as well as spinal-systemic combination of morphine (Niv et al., 1995) produced a supra-additive antinociceptive effect. Thus one can see that simultaneous activation of differ- ent antinociceptive mechanisms located either at the same or different levels of the CNS results in supra-additivity. This approach is obviously very promising because the doses of drugs in the combination may be reduced so that the incidence of side-effects might be lessened. Even more promising would be the combination of drugs which in addition to synergistic interaction of the desired effects would interact in an antagonistic manner in regard to their side effects. Anticholinesterase physostig- Pain 70 (1997) 217–221 0304-3959/97/$17.00  1997 International Association for the Study of Pain. Published by Elsevier Science B.V. PII S03043959(97)03326-5 * Corresponding author. Tel.: +1 213 3422138; fax: +1 213 2262794; e-mail: nemirovs@hsc.usc.edu