Muscarinic M1 and M3 receptor changes in the brain stem during pancreatic regeneration were investigated. Brain stem acetylcholine esterase activity decreased at the time of regeneration. Sympathetic activity also decreased as indicated by the norepinephrine (NE) and epinephrine (EPI) content of adrenals and also in the plasma. Muscarinic M1 and M3 receptors showed reciprocal changes in the brain stem during regeneration. Muscarinic M1 receptor number decreased at time of regeneration without any change in the affinity. High affinity M3 receptors showed an increase in the number. The affinity did not show any change. The number of low affinity receptors decreased with decreased Kd at 72 hours after partial pancreatectomy. The Kd reversed to control value with a reversal of the number of receptors to near control value. Gene expression studies also showed a similar change in the mRNA level of M1 and M3 receptors. These alterations in the muscarinic receptors regulate sympathetic activity and maintain glucose level during pancreatic regeneration. Central muscarinic M1 and M3 receptor subtypes functional balance is suggested to regulate sympathetic and parasympathetic activity, which in turn control the islet cell proliferation and glucose homeostasis.